Organic compounds

ABSTRACT

The present invention relates to optionally substituted 4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-(1H or 2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or 4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-(1H or 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, and methods of using said compound, e.g., wherein the treatment relates to diseases involving disorders of the dopamine D1 receptor intracellular pathway, such as, among others, Parkinson&#39;s disease, depression, narcolepsy, damage to cognitive function, e.g., in schizophrenia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a United States Application under 35 U.S.C. 371claiming benefit of PCT Application No. PCT/US2011/038527, filed on May31, 2011, which claims priority from U.S. Provisional Application No.61/349,952, filed on May 31, 2010, the contents of each of which arehereby incorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to optionally substituted4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-(1H or2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-(1H or2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, preferablyCompounds of Formula I as described below, processes for theirproduction, their use as pharmaceuticals and pharmaceutical compositionscomprising them. Of particular interest are novel compounds useful asinhibitors of phosphodiesterase 1 (PDE1), e.g., in the treatment ofdiseases involving disorders of the dopamine D1 receptor intracellularpathway, such as, among others, Parkinson's disease, depression,narcolepsy, damage to cognitive function, e.g., in schizophrenia, ordisorders that may be ameliorated through enhancedprogesterone-signaling pathway, e.g., female sexual dysfunction.

BACKGROUND OF THE INVENTION

Eleven families of phosphodiesterases (PDEs) have been identified butonly PDEs in Family I, the Ca²⁺-calmodulin-dependent phosphodiesterases(CaM-PDEs), have been shown to mediate both the calcium and cyclicnucleotide (e.g. cAMP and cGMP) signaling pathways. The three knownCaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed in centralnervous system tissue. PDE1A is expressed throughout the brain withhigher levels of expression in the CA1 to CA3 layers of the hippocampusand cerebellum and at a low level in the striatum. PDE1A is alsoexpressed in the lung and heart. PDE1B is predominately expressed in thestriatum, dentate gyrus, olfactory tract and cerebellum, and itsexpression correlates with brain regions having high levels ofdopaminergic innervation. Although PDE1B is primarily expressed in thecentral nervous system, it may be detected in the heart. PDE1C isprimarily expressed in olfactory epithelium, cerebellar granule cells,and striatum. PDE1C is also expressed in the heart and vascular smoothmuscle.

Cyclic nucleotide phosphodiesterases decrease intracellular cAMP andcGMP signaling by hydrolyzing these cyclic nucleotides to theirrespective inactive 5′-monophosphates (5′ AMP and 5′ GMP). CaM-PDEs playa critical role in mediating signal transduction in brain cells,particularly within an area of the brain known as the basal ganglia orstriatum. For example, NMDA-type glutamate receptor activation and/ordopamine D2 receptor activation result in increased intracellularcalcium concentrations, leading to activation of effectors such ascalmodulin-dependent kinase II (CaMKII) and calcineurin and toactivation of CaM-PDEs, resulting in reduced cAMP and cGMP. Dopamine D1receptor activation, on the other hand, leads to activation ofnucleotide cyclases, resulting in increased cAMP and cGMP. These cyclicnucleotides in turn activate protein kinase A (PKA; cAMP-dependentprotein kinase) and/or protein kinase G (PKG; cGMP-dependent proteinkinase) that phosphorylate downstream signal transduction pathwayelements such as DARPP-32 (dopamine and cAMP-regulated phosphoprotein)and cAMP responsive element binding protein (CREB). PhosphorylatedDARPP-32 in turn inhibits the activity of protein phosphates-1 (PP-1),thereby increasing the state of phosphorylation of substrate proteinssuch as progesterone receptor (PR), leading to induction of physiologicresponses. Studies in rodents have suggested that inducing cAMP and cGMPsynthesis through activation of dopamine D1 or progesterone receptorenhances progesterone signaling associated with various physiologicalresponses, including the lordosis response associated with receptivityto mating in some rodents. See Mani, et al., Science (2000) 287: 1053,the contents of which are incorporated herein by reference.

CaM-PDEs can therefore affect dopamine-regulated and other intracellularsignaling pathways in the basal ganglia (striatum), including but notlimited to nitric oxide, noradrenergic, neurotensin, CCK, VIP,serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA,acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor,natriuretic peptide (e.g., ANP, BNP, CNP), DARPP-32, and endorphinintracellular signaling pathways.

Phosphodiesterase (PDE) activity, in particular, phosphodiesterase 1(PDE1) activity, functions in brain tissue as a regulator of locomotoractivity and learning and memory. PDE1 is a therapeutic target forregulation of intracellular signaling pathways, preferably in thenervous system, including but not limited to a dopamine D1 receptor,dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK,VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA,acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor,natriuretic peptide (e.g., ANP, BNP, CNP), endorphin intracellularsignaling pathway and progesterone signaling pathway. For example,inhibition of PDE1B should act to potentiate the effect of a dopamine D1agonist by protecting cGMP and cAMP from degradation, and shouldsimilarly inhibit dopamine D2 receptor signaling pathways, by inhibitingPDE1 activity. Chronic elevation in intracellular calcium levels islinked to cell death in numerous disorders, particularly inneurodegenerative diseases such as Alzheimer's, Parkinson's andHuntington's Diseases and in disorders of the circulatory system leadingto stroke and myocardial infarction. PDE1 inhibitors are thereforepotentially useful in diseases characterized by reduced dopamine D1receptor signaling activity, such as Parkinson's disease, restless legsyndrome, depression, narcolepsy and cognitive impairment. PDE1inhibitors are also useful in diseases that may be alleviated by theenhancement of progesterone-signaling such as female sexual dysfunction.

There is thus a need for compounds that selectively inhibit PDE1activity, especially PDE1A and/or PDE1B activity.

SUMMARY OF THE INVENTION

The invention provides optionally substituted4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-(1H or2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-(1H or2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, in free or saltform, e.g., optionally substituted:

-   4,5,7,8-tetrahydro-(1H or    2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,-   4,5,7,8-tetrahydro-(1H or    2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-one,-   4,5,7,8-tetrahydro-(1H or    2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione,-   4,5,7,8-tetrahydro-(1H or    2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,-   4,5,7,8,9-pentahydro-(1H or    2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine,-   4,5,7,8,9-pentahydro-(1H or    2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-one,-   4,5,7,8,9-pentahydro-(1H or    2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione,-   4,5,7,8,9-pentahydro-(1H or    2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,    -   in free or salt form, preferably (1 or 2 and/or 3 and/or 5)        substituted, more preferably with 3-oxy-substituted compounds.

In another embodiment, the invention provides a Compound of Formula I:

wherein

-   -   (i) Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or CH₂;    -   (ii) L is a —O—;    -   (iii) R₁ is H or C₁₋₄alkyl (e.g., methyl or ethyl);    -   (iv) R₄ is H or C₁₋₄alkyl (e.g., methyl or isopropyl) and R₂ and        R₃ are, independently:        -   H,        -   C₁₋₆alkyl (e.g., methyl or isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together with the carbon to which they are            attached form a 3- to 6-membered ring; or        -   R₂ is H and R₃ and R₄ together form a di-, tri- or            tetra-methylene bridge,        -   (pref. wherein the R₃ and R₄ together have the cis            configuration, e.g., where the carbons carrying R₃ and R₄            have the R and S configurations, respectively);    -   (v) R₅ is        -   a) -D-E-F, wherein:            -   D is a single bond, C₁₋₄alkylene (e.g., methylene,                ethylene or prop-2-yn-1-ylene) or —C(═O)—;            -   E is a single bond, C₁₋₄alkylene (e.g., methylene,                —C≡C—), arylene (e.g., phenylene), arylC₁₋₄alkylene                (e.g., benzylene) or heteroarylene (e.g., pyridylene);                and            -   F is                -   H,                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                    example, pyrid-2-yl, imidazol-1-yl, pyrazol-1-yl,                    1,2,4-triazol-1-yl),                -   halo (e.g., F, Br, Cl),                -   C₁₋₄alkyl (e.g., methyl),                -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                -   haloC₁₋₄alkoxy,                -   C₁₋₄alkoxy (e.g., methoxy),                -   —C(O)—R₁₅,                -   —N(R₁₆)(R₁₇),                -   —S(O)₂R₂₁,                -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl), or                    heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl (for                    example, pyrrolidin-1-yl, pyrrolidin-2-yl or                    pyrrolidin-3-yl), piperidinyl (e.g.,                    piperidin-2-yl), tetrahydro-2H-pyran-4-yl or                    morpholinyl);            -   wherein D, E and F are independently and optionally                substituted with one or more group selected from:                -   halo (e.g., F, Cl or Br),                -   C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl),                    haloC₁₋₄alkyl (e.g., trifluoromethyl), and                    C₁₋₄alkoxy (methoxy),            -   for example, F is heteroaryl (e.g., pyridyl (for example                pyrid-2-yl, pyrid-3-yl, pyrid-4-yl), thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl                or pyrazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl),                tetrazolyl or oxadiazolyl (e.g., 1,2,4-oxodiazol-3-yl)                optionally substituted with one or more group selected                from halo and C₁₋₆alkyl (e.g., 4-methyl-imidazol-1-yl,                1-methyl-imidazol-2-yl, 5-fluoropyrid-2-yl,                6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,                4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),            -   or F is aryl, e.g., phenyl, optionally substituted with                one or more halo (e.g., 4-fluorophenyl);            -   or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl)                optionally substituted with a C₁₋₆alkyl (e.g.,                1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,                1-ethylpiperidin-1-yl or 1-methylpiperidin-2-yl);        -   b) a substituted heteroarylC₁₋₄alkyl, e.g., substituted with            haloC₁₋₄alkyl;        -   or        -   c) attached to one of the nitrogen atoms on the pyrazolo            portion of Formula I and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H, halogen (e.g., Cl or F),            —C₁₋₄alkyl-N(R₂₂)(R₂₃) (e.g., aminomethyl,            isopropylaminomethyl or isobutylaminomethyl), or            —C₁₋₄alkyl-heterC₃₋₈cycloalkyl (e.g.,            pyrrolidin-1-ylmethyl), and R₁₀ is:            -   hydrogen,            -   halogen (chloro or fluoro),            -   C₁₋₄alkyl,            -   haloC₁₋₄alkyl (e.g., trifluoromethyl), haloC₁₋₄alkoxy                (e.g., trifluoromethoxy),            -   C₁₋₄alkoxy,            -   C₃₋₇cycloalkyl,            -   hetC₃₋₇cycloalkyl (e.g., pyrrolidinyl or piperidinyl,                for example piperidin-2-yl or pyrrolidin-2-yl),            -   C₁₋₄haloalkyl (e.g., trifluoromethyl),            -   aryl (e.g., phenyl),            -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl,                pyrid-3-yl, pyrid-4-yl), thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl                or pyrazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl),                tetrazolyl or oxodiazolyl (e.g., 1,2,4-oxodiazol-3-yl),            -   arylcarbonyl (e.g., benzoyl),            -   C₁₋₄alkylsulfonyl (e.g., methylsulfonyl),            -   aminosulfonyl (e.g., —S(O)₂—N(R₁₈)(R₁₉),            -   heteroarylcarbonyl,            -   C₁₋₄alkylcarbonyl (e.g., methylcarbonyl),            -   C₁₋₄alkoxycarbonyl, (e.g., —C(O)OCH₃),            -   —C(O)OH,            -   haloC₁₋₄alkoxycarbony (e.g., trifluoromethylcarbonyl),            -   —C(O)N(R₁₈)(R₁₉), or            -   —C₁₋₄alkyl-N(R₁₈)(R₁₉) (e.g., methylaminomethyl),        -   wherein the aryl, heteroaryl, cycloalkyl and            heterocycloalkyl are independently and optionally            substituted with one or more group selected from halo (e.g.,            F or Cl), C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl),            C₁₋₄alkoxy, C₁₋₄haloalkyl (e.g., trifluoromethyl) and —SH;        -   For example, R₁₀ is phenyl, pyridyl, pyrazolyl, piperidinyl,            pyrrolidinyl oxadiazolyl pyrimidinyl, optionally substituted            with one or more group selected from halo (e.g., F or Cl),            C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl), C₁₋₄alkoxy,            C₁₋₄haloalkyl (e.g., trifluoromethyl) and —SH, e.g.            optionally substituted with halo or C₁₋₄alkyl, for example            R₁₀ is 1-methylpiperidin-2-yl, piperidin-2-yl,            1-ethylpiperidin-2-yl, 1-methylpyrrolidin-2-yl,            1-methylimidazol-2-yl, halopyridyl (for example            6-fluoropyrid-2-yl),        -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀,            respectively, is not present;

    -   (vi) R₆ is        -   C₁₋₄alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₄alkyl (e.g., benzyl),            -   wherein the aryl or heteroaryl is optionally substituted                with one or more group selected from halo (e.g., F, Cl),                hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for                example, R₆ is 3-chlorophenyl or 4-fluorophenyl,

    -   (vii) n=0 or 1;

    -   (viii) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H, C₁₋₄alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₄alkoxy or (optionally hetero)arylC₁₋₄alkyl or R₁₃        or R₁₄ can form a di-, tri- or tetramethylene bridge with R₂ or        R₄;

    -   (ix) R₁₅ is C₁₋₄alkyl (e.g., methyl), haloC₁₋₄alkyl (e.g.,        trifluoromethyl), —OH, —OC₁₋₄alkyl (e.g., —OCH₃), aryl (e.g.,        phenyl) or —N(R₁₆)(R₁₇);

    -   (x) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xi) R₁₈ and R₁₉ are independently        -   H,        -   C₁₋₄alky,        -   C₃₋₈cycloalkyl,        -   heteroC₃₋₈cycloalkyl,        -   aryl (e.g., phenyl), or        -   heteroaryl,        -   wherein said aryl or heteroaryl is optionally substituted            with one or more group selected from:            -   halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),            -   hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or                2-hydroxyphenyl),            -   C₁₋₆alkyl,            -   haloC₁₋₆alkyl,            -   C₁₋₆alkoxy,            -   aryl,            -   heteroaryl, and            -   C₃₋₈cycloalkyl;

    -   (xii) R₂₀ is H, C₁₋₄alkyl (e.g., methyl) or C₃₋₇cycloalkyl;

    -   (xiii) R₂₁ is C₁₋₆alkyl (e.g., methyl) or —N(R₁₈)(R₁₉);

    -   (xiv) R₂₂ and R₂₃ are independently H or C₁₋₄alkyl (e.g.,        methyl),

in free or salt form.

In another embodiment, the invention provides a Compound of Formula I asfollows:

-   -   1.1 Formula I, wherein Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or        CH₂;    -   1.2 Formula I or 1.1, wherein Q is —C(═S)—;    -   1.3 Formula I or 1.1, wherein Q is —C(═O)—    -   1.4 Formula I or 1.1, wherein Q is —C(═N(R₂₀))—;    -   1.5 Formula I or 1.1, wherein Q is —CH₂—;    -   1.6 Formula I, or any of 1.1-1.5, wherein R₁ is H or C₁₋₄alkyl        (e.g., methyl or ethyl);    -   1.7 Formula 1.6, wherein R₁ is H,    -   1.8 Formula 1.6, wherein R₁ is C₁₋₄alkyl (e.g., methyl or        ethyl);    -   1.9 Formula I, or any of 1.1-1.8, wherein R₄ is H or C₁₋₄alkyl        (e.g., methyl, isopropyl) and R₂ and R₃ are, independently:        -   H,        -   C₁₋₆alkyl (e.g., methyl or isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylC₁₋₆alkoxy,        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together with the carbon to which they are            attached form a 3- to 6-membered ring;        -   or        -   R₂ is H and R₃ and R₄ together form a di-, tri- or            tetramethylene bridge,        -   (pref. wherein the R₃ and R₄ together have the cis            configuration, e.g., where the carbons carrying R₃ and R₄            have the R and S configurations, respectively)    -   1.10 Formula 1.9, wherein R₂ or R₃ is H or C₁₋₆alkyl (e.g.,        methyl or isopropyl);    -   1.11 Formula 1.9, wherein R₂ or R₃ is H,    -   1.12 Formula 1.9, wherein R₂ or R₃ is C₁₋₆alkyl (e.g., methyl or        isopropyl);    -   1.13 Formula 1.9, wherein R₂ or R₃ is methyl;    -   1.14 Formula 1.9, wherein R₂ or R₃ is isopropyl;    -   1.15 Formula I, or any of 1.1-1.8, wherein R₂ is H and R₃ and R₄        together form a di-, tri- or tetramethylene bridge (pref.        wherein the R₃ and R₄ together have the cis configuration, e.g.,        where the carbons carrying R₃ and R₄ have the R and S        configurations, respectively);    -   1.16 Formula I or any of 1.1-1.15, wherein R₅ is -D-E-F;    -   1.17 Formula 1.16, wherein D is a single bond, C₁₋₄alkylene        (e.g., methylene, ethylene or prop-2-yn-1-ylene) or —C(═O)—;    -   1.18 Formula 1.17, wherein D is a single bond;    -   1.19 Formula 1.17, wherein D is C₁₋₄alkylene (e.g., methylene,        ethylene or prop-2-yn-1-ylene);    -   1.20 Formula 1.17, wherein D is methylene;    -   1.21 Any of formulae 1.16-1.20, wherein E is a single bond,        C₁₋₄alkylene (e.g., methylene, —C≡C—), arylene (e.g.,        phenylene), arylC₁₋₄alkylene (e.g., benzylene) or heteroarylene        (e.g., pyridylene);    -   1.22 Any of formulae 1.16-1.20, wherein E is arylene (e.g.,        phenylene);    -   1.23 Any of formulae 1.16-1.20, wherein E is phenylene;    -   1.24 Any of formulae 1.16-1.20, wherein E is heteroarylene        (e.g., pyridylene);    -   1.25 Any of formulae 1.16-1.20, wherein E is C₁₋₄alkylene (e.g.,        methylene, —C≡C—);    -   1.26 Any of formulae 1.16-1.20, wherein E is arylC₁₋₄alkylene        (e.g., benzylene);    -   1.27 Any of formulae 1.16-1.20, wherein E is a single bond;    -   1.28 Any of formulae 1.16-1.27, wherein F is        -   H,        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for example,            pyrid-2-yl, pyrid-4-yl, pyrid-3-yl, imidazol-1-yl,            pyrazol-1-yl, 1,2,4-triazol-1-yl),        -   halo (e.g., F, Br, Cl),        -   haloC₁₋₄alkyl (e.g., trifluoromethyl),        -   haloC₁₋₄alkoxy,        -   C₁₋₄alkoxy (e.g., methoxy),        -   —C(O)—R₁₅,        -   —N(R₁₆)(R₁₇),        -   —S(O)₂R₂₁,        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl), or        -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl (for example,            pyrrolidin-1-yl, pyrrolidin-2-yl or pyrrolidin-3-yl),            piperidinyl (e.g., piperidin-2-yl), tetrahydro-2H-pyran-4-yl            or morpholinyl);        -   wherein F is optionally substituted with one or more group            selected from:            -   halo (e.g., F, Cl or Br),            -   C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl),            -   haloC₁₋₄alkyl (e.g., trifluoromethyl),            -   C₁₋₄alkoxy, and            -   C₁₋₄alkyl (e.g., 5-methylpyrid-2-yl),            -   for example, F is heteroaryl (e.g., pyridyl, pyrazolyl                or imidazolyl), aryl (e.g., phenyl) or                heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl (for example,                pyrrolidin-1-yl, pyrrolidin-2-yl or pyrrolidin-3-yl),                piperidinyl (e.g., piperidin-2-yl),                tetrahydro-2H-pyran-4-yl or morpholinyl), optionally                substituted with one or more halo (e.g., F, Cl or Br),                C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl),                haloC₁₋₄alkyl (e.g., trifluoromethyl), C₁₋₄alkoxy) or                C₁₋₄alkyl (for example, F is 5-methylpyrid-2-yl,                4-methyl-imidazol-1-yl, 1-methyl-imidazol-2-yl,                5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                4,6-dichloropyrid-2-yl, 4-fluorophenyl,                1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,                1-ethylpiperidin-1-yl or 1-methylpiperidin-2-yl);    -   1.29 Formula 1.28, wherein F is H;    -   1.30 Formula 1.28, wherein F is haloC₁₋₄alkyl (e.g.,        trifluoromethyl);    -   1.31 Formula 1.28, wherein F is trifluoromethyl;    -   1.32 Formula 1.28, wherein F is halo (e.g., F, Br or Cl);    -   1.33 Formula 1.28, wherein F is Cl;    -   1.34 Formula 1.28, wherein F is heteroaryl (e.g., pyridyl (for        example pyrid-2-yl, pyrid-3-yl, pyrid-4-yl), or thiadiazolyl        (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl or        pyrazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl        or oxadiazolyl (e.g., 1,2,4-oxodiazol-3-yl) optionally        substituted with one or more halo (e.g., F, Cl or Br), C₁₋₄alkyl        (e.g., methyl or prop-2-yn-1-yl), haloC₁₋₄alkyl (e.g.,        trifluoromethyl), C₁₋₄alkoxy or C₁₋₄alkyl, (e.g.,        5-trifluoromethylpyrid-2-yl, 4-methyl-imidazol-1-yl,        1-methyl-imidazol-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,        3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl);    -   1.35 Formula 1.28, wherein F is heteroaryl (e.g., pyridyl,        diazolyl, triazolyl, for example, pyrid-2-yl, pyrid-4-yl,        pyrid-3-yl, imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl)        optionally substituted with one or more halo (e.g., F, Cl or        Br), C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl), haloC₁₋₄alkyl        (e.g., trifluoromethyl), C₁₋₄alkoxy) or C₁₋₄alkyl;    -   1.36 Any Formulae 1.34-1.35, wherein F is pyrid-2-yl (e.g.,        pyrid-2-yl, pyrid-3-yl, pyrid-4-yl);    -   1.37 Formula 1.34, wherein F is pyridyl (e.g., pyrid-2-yl,        pyrid-3-yl, pyrid-4-yl) optionally substituted with one or more        halo (e.g., phenyl, 4-fluorophenyl or 3-chlorophenyl);    -   1.38 Formula 1.34 or 1.37, wherein F is 6-fluoropyrid-2-yl;    -   1.39 Formula 1.34 or 1.37, wherein F is 3-fluoropyrid-2-yl;    -   1.40 Formula 1.34 or 1.37, wherein F is 4-fluoropyrid-2-yl;    -   1.41 Formula 1.34, wherein F is 5-fluoropyrid-2-yl;    -   1.42 Formula 1.34, wherein F is 5-trifluoromethylpyrid-2-yl;    -   1.43 Formula 1.34, wherein F is 5-methylpyrid-2-yl;    -   1.44 Formula 1.34, wherein F is 6-thio-pyrid-2-yl;    -   1.45 Formula 1.34, wherein F is 1,2,4-triazolyl (e.g.,        1,2,4-triazolyl);    -   1.46 Any Formulae 1.34-1.35, wherein F is diazolyl (e.g.,        imidazol-1-yl or pyrazol-1-yl);    -   1.47 Formula 1.34, wherein F is imidazol-1-yl or pyrazol-1-yl;    -   1.48 Formula 1.34, wherein F is aryl (e.g., phenyl) optionally        substituted with one or more:        -   halo (e.g., F, Cl or Br),        -   C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl),        -   haloC₁₋₄alkyl (e.g., trifluoromethyl),        -   C₁₋₄alkoxy or        -   C₁₋₄alkyl (e.g., 5-methylpyrid-2-yl);    -   1.49 Formula 1.34 or 1.47, wherein F is phenyl optionally        substituted with the substituents set forth in formula 1.47;    -   1.50 Formula 1.34 or 1.47, wherein F is 4-fluorophenyl or        3-chlorophenyl;    -   1.51 Formula 1.34, wherein F is C₃₋₇cycloalkyl (e.g.,        cyclopentyl, cyclohexyl) optionally substituted with one or more        halo (e.g., F, Cl or Br), C₁₋₄alkyl (e.g., methyl or        prop-2-yn-1-yl), haloC₁₋₄alkyl (e.g., trifluoromethyl),        C₁₋₄alkoxy or C₁₋₄alkyl;    -   1.52 Formula 1.51, wherein F is cyclohexyl;    -   1.53 Formula 1.51, wherein F is cyclopentyl;    -   1.54 Formula 1.28, wherein F is heteroC₃₋₇cycloalkyl (e.g.,        pyrrolidinyl (for example, pyrrolidin-1-yl, pyrrolidin-2-yl or        pyrrolidin-3-yl), piperidinyl (e.g., piperidin-2-yl),        tetrahydro-2H-pyran-4-yl or morpholinyl) optionally substituted        with one or more halo (e.g., F, Cl or Br), C₁₋₄alkyl (e.g.,        methyl or prop-2-yn-1-yl), haloC₁₋₄alkyl (e.g.,        trifluoromethyl), C₁₋₄alkoxy or C₁₋₄alkyl;    -   1.55 Formula 1.54, wherein F is pyrrolidinyl (e.g.,        pyrrolidin-3-yl, pyrrolidin-2-yl or pyrrolidin-1-yl) optionally        substituted with one or more C₁₋₄alkyl;    -   1.56 Formula 1.54, wherein F is 1-methylpyrrolidinyl or        1-ethylpyrrolidinyl;    -   1.57 Formula 1.54, wherein F is piperidinyl (e.g.,        piperidin-2-yl) optionally substituted with one or more halo        (e.g., F, Cl or Br), C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl),        haloC₁₋₄alkyl (e.g., trifluoromethyl), C₁₋₄alkoxy or C₁₋₄alkyl;    -   1.58 Formula 1.54 or 1.57, wherein F is piperidinyl (e.g.,        piperidin-2-yl) optionally substituted with C₁₋₄alkyl (e.g.,        methyl or prop-2-yn-1-yl);    -   1.59 Formula 1.54 or 1.57, wherein F is 1-methylpiperidin-2-yl        or 1-ethylpiperidin-2-yl;    -   1.60 Formula 1.54, wherein F is tetrahydro-2H-pyran-4-yl;    -   1.61 Formula 1.28, wherein F is aryl (e.g., phenyl) optionally        substituted with one or more halo (e.g., F, Cl or Br), C₁₋₄alkyl        (e.g., methyl or prop-2-yn-1-yl), haloC₁₋₄alkyl (e.g.,        trifluoromethyl), C₁₋₄alkoxy or C₁₋₄alkyl;    -   1.62 Formula 1.61, wherein F is phenyl;    -   1.63 Formula 1.61, wherein F is 4-fluorophenyl;    -   1.64 Formula 1.28, wherein F is —S(O)₂R₂₁ wherein R₂₁ is        C₁₋₆alkyl (e.g., methyl) or —N(R₁₈)(R₁₉);    -   1.65 Formula 1.64, wherein R₂₁ is C₁₋₆alkyl (e.g., methyl);    -   1.66 Formula 1.64, wherein R₂₁ is —N(R₁₈)(R₁₉);    -   1.67 Formula 1.28, wherein F is —C(O)—R₁₅ and R₁₅ is C₁₋₄alkyl        (e.g., methyl), haloC₁₋₄alkyl (e.g., trifluoromethyl), —OH,        —OC₁₋₄alkyl (e.g., —OCH₃), aryl (e.g., phenyl) or —N(R₁₆)(R₁₇);    -   1.68 Formula 1.28, wherein F is —C(O)—R₁₅ and R₁₅ is C₁₋₄alkyl        (e.g., methyl), haloC₁₋₄alkyl (e.g., trifluoromethyl), —OH,        —OC₁₋₄alkyl (e.g., —OCH₃), aryl (e.g., phenyl) or —N(R₁₆)(R₁₇);    -   1.69 Formula 1.68, wherein R₁₅ is C₁₋₄alkyl (e.g., methyl);    -   1.70 Formula 1.68, wherein R₁₅ is haloC₁₋₄alkyl (e.g.,        trifluoromethyl);    -   1.71 Formula 1.68, wherein R₁₅ is —OH;    -   1.72 Formula 1.68, wherein R₁₅ is —OC₁₋₄alkyl (e.g., methoxy or        ethoxy);    -   1.73 Formula 1.68, wherein R₁₅ is ethoxy;    -   1.74 Formula 1.28, wherein F is —N(R₁₆)(R₁₇);    -   1.75 Any of formulae 1.16-1.74, wherein D, E and F are        independently and optionally substituted with one or more:        -   halo (e.g., F, Cl or Br),        -   C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl),        -   haloC₁₋₄alkyl (e.g., trifluoromethyl), or        -   C₁₋₄alkoxy (methoxy);    -   1.76 Formula I or any of 1.1-1.15, wherein R₅ is a substituted        heteroarylalkyl, e.g., substituted with haloalkyl;    -   1.77 Formula I or any of 1.1-1.15, wherein R₅ is attached to one        of the nitrogen atoms on the pyrazolo portion of Formula I and        is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H, halogen (e.g., Cl or F),            —C₁₋₄alkyl-N(R₂₂)(R₂₃) (e.g., aminomethyl,            isopropylaminomethyl or isobutylaminomethyl), or            —C₁₋₄alkyl-heterC₃₋₈cycloalkyl (e.g.,            pyrrolidin-1-ylmethyl), and R₁₀ is:            -   hydrogen,            -   halogen (chloro or fluoro),            -   C₁₋₄alkyl,            -   haloC₁₋₄alkyl (e.g., trifluoromethyl),            -   haloC₁₋₄alkoxy (e.g., trifluoromethoxy),            -   C₁₋₄alkoxy,            -   C₃₋₇cycloalkyl,            -   hetC₃₋₇cycloalkyl (e.g., pyrrolidinyl or piperidinyl,                for example piperidin-2-yl or pyrrolidin-2-yl),            -   C₁₋₄haloalkyl (e.g., trifluoromethyl),            -   aryl (e.g., phenyl),            -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl,                pyrid-3-yl, pyrid-4-yl), thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl                or pyrazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl),                tetrazolyl or oxodiazolyl (e.g., 1,2,4-oxodiazol-3-yl),            -   arylcarbonyl (e.g., benzoyl),            -   C₁₋₄alkylsulfonyl (e.g., methylsulfonyl),            -   aminosulfonyl (e.g., —S(O)₂—N(R₁₈)(R₁₉),            -   heteroarylcarbonyl,            -   C₁₋₄alkylcarbonyl (e.g., methylcarbonyl),            -   C₁₋₄alkoxycarbonyl, (e.g., —C(O)OCH₃),            -   —C(O)OH,            -   haloC₁₋₄alkoxycarbony (e.g., trifluoromethylcarbonyl),            -   —C(O)N(R₁₁)(R₁₉), or            -   —C₁₋₄alkyl-N(R₁₈)(R₁₉) (e.g., methylaminomethyl),        -   wherein the aryl, heteroaryl, cycloalkyl and            heterocycloalkyl are independently and optionally            substituted with one or more group selected from halo (e.g.,            F or Cl), C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl),            C₁₋₄alkoxy, C₁₋₄haloalkyl (e.g., trifluoromethyl) and —SH;        -   For example, R₁₀ is phenyl, pyridyl, pyrazolyl, piperidinyl,            pyrrolidinyl oxadiazolyl pyrimidinyl, optionally substituted            with one or more group selected from halo (e.g., F or Cl),            C₁₋₄alkyl (e.g., methyl or prop-2-yn-1-yl), C₁₋₄alkoxy,            C₁₋₄haloalkyl (e.g., trifluoromethyl) and —SH, e.g.            optionally substituted with halo or C₁₋₄alkyl, for example            R₁₀ is 1-methylpiperidin-2-yl, piperidin-2-yl,            1-ethylpiperidin-2-yl, 1-methylpyrrolidin-2-yl,            1-methylimidazol-2-yl, halopyridyl (for example            6-fluoropyrid-2-yl),        -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀,            respectively, is not present;

    -   1.78 Formula 1.77, wherein R₅ is a substituted heteroarylmethyl,        e.g., para-substituted with haloalkyl;

    -   1.79 Formula 1.77, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is phenyl;

    -   1.80 Formula 1.77, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are H and R₁₀ is pyridyl or thiadiazolyl;

    -   1.81 Formula 1.77, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are, independently, H or halogen, and R₁₀        is haloalkyl;

    -   1.82 Formula 1.77, wherein R₅ is a moiety of Formula A wherein        R₈, R₉, R₁₁, and R₁₂ are, independently, H, and R₁₀ is alkyl        sulfonyl;

    -   1.83 Formula I or any of 1.1-1.82, wherein R₆ is        -   C₁₋₄alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), or        -   arylC₁₋₄alkyl (e.g., benzyl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more group selected from halo (e.g., F, Cl),            hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, for            example, R₆ is 3-chlorophenyl or 4-fluorophenyl;

    -   1.84 Formula 1.83, wherein R₆ is C₁₋₄alkyl (e.g., isopropyl);

    -   1.85 Formula 1.83, wherein R₆ is C₃₋₇cycloalkyl (e.g.,        cyclopentyl or cyclohexyl);

    -   1.86 Formula 1.83, wherein R₆ is heteroaryl (e.g., pyridyl, for        example, pyrid-4-yl);

    -   1.87 Formula 1.83, wherein R₆ is arylC₁₋₄alkyl (e.g., benzyl);

    -   1.88 Formula 1.83, wherein R₆ is aryl (e.g., phenyl) optionally        substituted with one or more group selected from halo (e.g., F,        Cl), hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl;

    -   1.89 Formula 1.83, wherein R₆ is fluorophenyl (e.g.,        4-fluorophenyl);

    -   1.90 Formula I or any of 1.1-1.89, wherein n=0;

    -   1.91 Formula I or any of 1.1-1.89, wherein n=1;

    -   1.92 Formula 1.91, wherein n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃        and R₁₄, are, independently, H or C₁₋₄alkyl, aryl, heteroaryl,        (optionally hetero)arylC₁₋₄alkoxy or (optionally        hetero)arylC₁₋₄alkyl;

    -   1.93 Formula I or any of 1.1-1.92, wherein R₁₆ and R₁₇ are        independently H or C₁₋₄alkyl;

    -   1.94 formula 1.93, wherein R₁₆ and R₁₇ are H,

    -   1.95 formula 1.93, wherein R₁₆ and R₁₇ are C₁₋₄alkyl;

    -   1.96 formula 1.93, wherein R₁₆ is H and R₁₇ is C₁₋₄alkyl;

    -   1.97 Formula I or any of 1.1-1.96, wherein R₁₈ and R₁₉ are        independently        -   H,        -   C₁₋₄alky,        -   C₃₋₈cycloalkyl,        -   heteroC₃₋₈cycloalkyl,        -   aryl (e.g., phenyl), or        -   heteroaryl,        -   wherein said aryl or heteroaryl is optionally substituted            with one or more group selected from:            -   halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),            -   hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or                2-hydroxyphenyl),            -   C₁₋₆alkyl,            -   haloC₁₋₆alkyl,            -   C₁₋₆alkoxy,            -   aryl,            -   heteroaryl, and            -   C₃₋₈cycloalkyl;

    -   1.98 Formula I or any of 1.1-1.97, wherein R₁₈ and R₁₉ are        independently H or C₁₋₄alkyl (e.g., methyl);

    -   1.99 Formula I or any of 1.1-1.98, wherein R₂₀ is H, C₁₋₄alkyl        (e.g., methyl) or C₃₋₇cycloalkyl;

    -   1.100 Formula 1.99, wherein R₂₀ is H,

    -   1.101 Formula 1.99, wherein R₂₀ is C₁₋₄alkyl (e.g., methyl);

    -   1.102 Formula 1.99, wherein R₂₀ is C₃₋₇cycloalkyl;

    -   1.103 Formula I or any of 1.1-1.102, wherein R₂₁ is C₁₋₆alkyl        (e.g., methyl) or —N(R₁₈)(R₁₉) and R₁₈ and R₁₉ are independently        H or C₁₋₄alkyl;

    -   1.104 Formula 1.103, wherein R₂₁ is C₁₋₆alkyl (e.g., methyl);

    -   1.105 Formula 1.103, wherein R₂₁ is —N(R₁₈)(R₁₉) and R₁₈ and R₁₉        are independently H or C₁₋₄alkyl;

    -   1.106 Formula I or any of 1.1-1.105, wherein R₂₂ and R₂₃ are        independently H or C₁₋₄alkyl (e.g., methyl);

    -   1.107 Formula 1.106, wherein R₂₂ and R₂₃ are H,

    -   1.108 Formula 1.106, wherein R₂₂ and R₂₃ are C₁₋₄alkyl (e.g.,        methyl);

    -   1.109 Formula 1.106, wherein R₂₂ is H and R₂₃ is C₁₋₄alkyl        (e.g., methyl);

    -   1.110 any of the preceding formulae wherein the compound is        selected from a group consisting of:

-   -   1.111 any of the preceding formulae wherein the compounds        inhibit phosphodiesterase-mediated (e.g., PDE1-mediated,        especially PDE1B-mediated) hydrolysis of cGMP, e.g., with an        IC₅₀ of less than 1 μM, preferably less than 500 nM, more        preferably less than 50 nM, still more preferably less than 10        nM, most preferably less than 1 nM in an immobilized-metal        affinity particle reagent PDE assay, for example, as described        in Example 12,

in free or salt form.

In one embodiment, the compound of formula I as described above, is acompound of Formula II:

wherein

-   -   (i) Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or CH₂;    -   (ii) L is a —O—;    -   (iii) R₁ is H or C₁₋₄alkyl (e.g., methyl or ethyl);    -   (iv) R₄ is H or C₁₋₄alkyl (e.g., methyl or isopropyl) and R₂ and        R₃ are, independently:        -   H,        -   C₁₋₆alkyl (e.g., methyl or isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylC₁₋₆alkoxy, or        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together with the carbon to which they are            attached form a 3- to 6-membered ring; or        -   R₂ is H and R₃ and R₄ together form a di-, tri- or            tetramethylene bridge        -   (pref. wherein the R₃ and R₄ together have the cis            configuration, e.g., where the carbons carrying R₃ and R₄            have the R and S configurations, respectively);    -   (v) R₅ is        -   a) -D-E-F, wherein            -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is arylene (e.g., phenylene); and            -   F is aryl (e.g., phenyl), heteroaryl (e.g., pyridyl,                diazolyl, triazolyl, for example, pyrid-2-yl,                imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl),                C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl), or                heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl (for example,                pyrrolidin-1-yl, pyrrolidin-2-yl or pyrrolidin-3-yl),                piperidinyl (e.g., piperidin-2-yl),                tetrahydro-2H-pyran-4-yl or morpholinyl), wherein F is                optionally substituted with one or more halo or                C₁₋₆alkyl (e.g., F is 4-methyl-imidazol-1-yl,                1-methyl-imidazol-2-yl, 5-fluoropyrid-2-yl,                6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,                4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl,                4-fluorophenyl, 1-methylpyrrolidin-3-yl,                1-methylpyrrolidin-2-yl, 1-ethylpiperidin-1-yl or                1-methylpiperidin-2-yl);        -   or        -   b) attached to one of the nitrogen atoms on the pyrazolo            portion of Formula II and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H, halogen (e.g., Cl or F),            and R₁₀ is C₃₋₇cycloalkyl, hetC₃₋₇cycloalkyl (e.g.,            pyrrolidinyl or piperidinyl, for example piperidin-2-yl or            pyrrolidin-2-yl), aryl (e.g., phenyl), or heteroaryl (e.g.,            pyridyl (for example pyrid-2-yl, pyrid-3-yl, pyrid-4-yl), or            thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,            imidazol-1-yl or pyrazol-1-yl), triazolyl (e.g.,            1,2,4-triazol-1-yl), tetrazolyl or oxadiazolyl (e.g.,            1,2,4-oxodiazol-3-yl), wherein the aryl, heteroaryl,            cycloalkyl and heterocycloalkyl are independently and            optionally substituted with one or more halo (e.g., F or Cl)            or C₁₋₄alkyl, for example R₁₀ is 4-methyl-imidazol-1-yl,            1-methyl-imidazol-2-yl, 5-fluoropyrid-2-yl,            6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,            4,6-dichloropyrid-2-yl, 4-fluorophenyl,            1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,            1-ethylpiperidin-1-yl or 1-methylpiperidin-2-yl;

    -   (vi) R₆ is        -   C₁₋₄alkyl (e.g., isopropyl or isobutyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),        -   arylC₁₋₄alkyl (e.g., benzyl),            -   wherein the aryl or heteroaryl is optionally substituted                with one or more halo (e.g., F, Cl), hydroxy, C₁₋₆alkyl,                C₁₋₆alkoxy, C₃₋₈cycloalkyl, for example, R₆ is                isopropyl, isobutyl, cyclopentyl, cyclohexyl, phenyl,                3-chlorophenyl or 4-fluorophenyl;

    -   (vii) n=0 or 1;

    -   (viii) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₄alkoxy, (optionally hetero)arylC₁₋₄alkyl or R₁₃        or R₁₄ can form a di-, tri- or tetramethylene bridge with R₂ or        R₄;

    -   (ix) R₂₀ is H, C₁₋₄alkyl (e.g., methyl) or C₃₋₇cycloalkyl,

in free or salt form.

In still another embodiment, the Compound of Formula I as describedabove is a Compound of Formula III:

wherein

-   -   (i) Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or CH₂;    -   (ii) L is a —O—;    -   (iii) R₁ is H or C₁₋₄alkyl (e.g., methyl or ethyl);    -   (iv) R₄ is H or C₁₋₄alkyl (e.g., methyl, isopropyl) and R₂ and        R₃ are, independently:        -   H,        -   C₁₋₆alkyl (e.g., methyl or isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylC₁₋₆alkoxy,        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together with the carbon to which they are            attached form a 3- to 6-membered ring; or        -   R₂ is H and R₃ and R₄ together form a di-, tri- or            tetramethylene bridge        -   (pref. wherein the R₃ and R₄ together have the cis            configuration, e.g., where the carbons carrying R₃ and R₄            have the R and S configurations, respectively);    -   (v) R₅ is        -   a) -D-E-F, wherein            -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is arylene (e.g., phenylene); and            -   F is aryl (e.g., phenyl), heteroaryl (e.g., pyridyl,                diazolyl, triazolyl, for example, pyrid-2-yl,                imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl),                C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl), or                heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl (for example,                pyrrolidin-1-yl, pyrrolidin-2-yl or pyrrolidin-3-yl),                piperidinyl (e.g., piperidin-2-yl),                tetrahydro-2H-pyran-4-yl or morpholinyl), wherein F is                optionally substituted with one or more halo or                C₁₋₆alkyl (e.g., F is 4-methyl-imidazol-1-yl,                1-methyl-imidazol-2-yl, 5-fluoropyrid-2-yl,                6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,                4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl,                4-fluorophenyl, 1-methylpyrrolidin-3-yl,                1-methylpyrrolidin-2-yl, 1-ethylpiperidin-1-yl or                1-methylpiperidin-2-yl);        -   or        -   b) attached to one of the nitrogen atoms on the pyrazolo            portion of Formula III and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F),            and R₁₀ is C₃₋₇cycloalkyl, hetC₃₋₇cycloalkyl (e.g.,            pyrrolidinyl or piperidinyl, for example piperidin-2-yl or            pyrrolidin-2-yl), aryl (e.g., phenyl), or heteroaryl (e.g.,            pyridyl (for example pyrid-2-yl, pyrid-3-yl, pyrid-4-yl), or            thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,            imidazol-1-yl or pyrazol-1-yl), triazolyl (e.g.,            1,2,4-triazol-1-yl), tetrazolyl, oxadiazolyl (e.g.,            1,2,4-oxodiazol-3-yl), wherein the aryl, heteroaryl,            cycloalkyl and heterocycloalkyl are independently and            optionally substituted with one or more halo (e.g., F or Cl)            or C₁₋₄alkyl;

    -   (vi) R₆ is:        -   C₁₋₄alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more halo (e.g., F or Cl), hydroxy or C₁₋₆alkyl,            for example, R₆ is 3-chlorophenyl or 4-fluorophenyl,

    -   (vii) n=0 or 1;

    -   (viii) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₄alkoxy, (optionally hetero)arylC₁₋₄alkyl or R₁₃        or R₁₄ can form a di-, tri- or tetramethylene bridge with R₂ or        R₄;

    -   (x) R₂₀ is H, C₁₋₄alkyl (e.g., methyl) or C₃₋₇cycloalkyl,

in free or salt form.

In still another embodiment of the invention, the Compound of Formula Iis a compound of Formula IV:

wherein:

-   -   (i) Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or CH₂;    -   (ii) L is a —O—;    -   (iii) R₁ is H or C₁₋₄alkyl (e.g., methyl or ethyl);    -   (iv) R₅ is        -   a) -D-E-F, wherein            -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is arylene (e.g., phenylene);            -   F is aryl (e.g., phenyl), heteroaryl (e.g., pyridyl,                diazolyl, triazolyl, for example, pyrid-2-yl,                imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl),                C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl), or                heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl (for example,                pyrrolidin-1-yl, pyrrolidin-2-yl or pyrrolidin-3-yl),                piperidinyl (e.g., piperidin-2-yl),                tetrahydro-2H-pyran-4-yl or morpholinyl), wherein F is                optionally substituted with one or more halo or                C₁₋₆alkyl (e.g., F is 4-methyl-imidazol-1-yl,                1-methyl-imidazol-2-yl, 5-fluoropyrid-2-yl,                6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,                4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl,                4-fluorophenyl, 1-methylpyrrolidin-3-yl,                1-methylpyrrolidin-2-yl, 1-ethylpiperidin-1-yl or                1-methylpiperidin-2-yl);        -   or        -   b) attached to one of the nitrogen atoms on the pyrazolo            portion of Formula IV and is a moiety of Formula A

-   -   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉,            R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F),            and R₁₀ is C₃₋₇cycloalkyl, hetC₃₋₇cycloalkyl (e.g.,            pyrrolidinyl or piperidinyl, for example piperidin-2-yl or            pyrrolidin-2-yl), aryl (e.g., phenyl), or heteroaryl (e.g.,            pyridyl (for example pyrid-2-yl, pyrid-3-yl, pyrid-4-yl), or            thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,            imidazol-1-yl or pyrazol-1-yl), triazolyl (e.g.,            1,2,4-triazol-1-yl), tetrazolyl, oxadiazolyl (e.g.,            1,2,4-oxodiazol-3-yl), wherein the aryl, heteroaryl,            cycloalkyl and heterocycloalkyl are independently and            optionally substituted with one or more halo (e.g., F or            Cl), C₁₋₄alkyl;

    -   (v) R₆ is:        -   C₁₋₄alkyl (e.g., isopropyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),        -   wherein the aryl or heteroaryl is optionally substituted            with one or more halo (e.g., F, Cl), hydroxy or C₁₋₆alkyl,            for example, R₆ is 3-chlorophenyl or 4-fluorophenyl,

    -   (xi) R₂₀ is H, C₁₋₄alkyl (e.g., methyl) or C₃₋₇cycloalkyl,

in free or salt form.

In yet another embodiment, the Compound of Formula I is a compound ofFormula V:

wherein:

-   -   (i) Q is —C(═O)—;    -   (ii) L is —O—;    -   (iii) R₁ is C₁₋₄alkyl (e.g., methyl or ethyl);    -   (iv) R₅ is attached to one of the nitrogen atoms on the pyrazolo        portion of Formula V and is a moiety of Formula A

-   -   -   wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are            independently H, and R₁₀ is:            -   hetC₃₋₇cycloalkyl (e.g., pyrrolidinyl or piperidinyl,                for example piperidin-2-yl or pyrrolidin-2-yl),            -   aryl (e.g., phenyl), or            -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl,                pyrid-3-yl, pyrid-4-yl), or thiadiazolyl (e.g.,                1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl                or pyrazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl),                tetrazolyl or oxadiazolyl (e.g., 1,2,4-oxodiazol-3-yl),            -   wherein the aryl, heteroaryl, cycloalkyl and                heterocycloalkyl are independently and optionally                substituted with one or more halo (e.g., F or Cl),                C₁₋₄alkyl, for example R₁₀ is 4-methyl-imidazol-1-yl,                1-methyl-imidazol-2-yl, 5-fluoropyrid-2-yl,                6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,                4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl,                4-fluorophenyl, 1-methylpyrrolidin-3-yl,                1-methylpyrrolidin-2-yl, 1-ethylpiperidin-1-yl or                1-methylpiperidin-2-yl;

    -   (v) R₆ is        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),        -   arylC₁₋₄alkyl (e.g., benzyl),            -   wherein the aryl or heteroaryl is optionally substituted                with one or more halo (e.g., F, Cl), hydroxy, C₁₋₆alkyl,                C₁₋₆alkoxy, C₃₋₈cycloalkyl, for example, R₆ is                isopropyl, isobutyl, cyclopentyl, cyclohexyl, phenyl,                3-chlorophenyl or 4-fluorophenyl,

in free or salt form.

In another embodiment, the Compound of Formula I is a compound ofFormula VI:

wherein:

-   -   (i) Q is —C(═O)—;    -   (ii) L is —O—;    -   (iii) R₁ is C₁₋₄alkyl (e.g., methyl or ethyl);    -   (iv) R₅ is attached to one of the nitrogen atoms on the pyrazolo        portion of Formula VI and is a moiety of Formula A

-   -   -   wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are            independently H, and R₁₀ is selected from piperidinyl (e.g.,            piperidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-2-yl),            pyridyl (for example pyrid-2-yl, pyrid-3-yl), diazolyl            (e.g., pyrazol-1-yl), 6-fluoropyrid-2-yl,            1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,            1-ethylpiperidin-1-yl or 1-methylpiperidin-2-yl;

    -   (v) R₆ is        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),        -   arylC₁₋₄alkyl (e.g., benzyl),            -   wherein the aryl or heteroaryl is optionally substituted                with one or more halo (e.g., F, Cl), hydroxy, C₁₋₆alkyl,                C₁₋₆alkoxy, C₃₋₈cycloalkyl,            -   for example, R₆ is cyclopentyl, cyclohexyl, phenyl,                3-chlorophenyl or 4-fluorophenyl,

in free or salt form.

In still another embodiment, the invention provides a Compound ofFormula VII:

wherein:

-   -   (i) Q is —C(═O)—;    -   (ii) L is —O—;    -   (iii) R₁ is C₁₋₄alkyl (e.g., methyl or ethyl);    -   (iv) R₅ is attached to one of the nitrogen atoms on the pyrazolo        portion of Formula VII and is a moiety of Formula A

-   -   -   wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are            independently H, and R₁₀ is selected from piperidinyl (e.g.,            piperidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-2-yl),            pyridyl (for example pyrid-2-yl, pyrid-3-yl), diazolyl            (e.g., pyrazol-1-yl), 6-fluoropyrid-2-yl,            1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,            1-ethylpiperidin-1-yl or 1-methylpiperidin-2-yl;

    -   (v) R₆ is selected from cyclopentyl, cyclohexyl, phenyl,        3-chlorophenyl or 4-fluorophenyl,

in free or salt form.

In still another embodiment, the invention provides a Compound ofFormula VIII:

wherein:

-   -   (i) Q is —C(═O)—;    -   (ii) L is —O—;    -   (iii) R₁ is C₁₋₄alkyl (e.g., methyl or ethyl);    -   (iv) R₅ is attached to one of the nitrogen atoms on the pyrazolo        portion of Formula VIII and is a moiety of Formula A

-   -   -   wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are            independently H, and R₁₀ is pyrid-2-yl, 6-fluoropyrid-2-yl,            1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,            1-ethylpiperidin-1-yl or 1-methylpiperidin-2-yl;

    -   (v) R₆ is phenyl or 4-fluorophenyl,

in free or salt form.

In still another embodiment, the invention provides a compound of any ofthe foregoing formulae, e.g., any of Formula I-VIII or any of formulae1.1-1.111, wherein R₁₀ is selected from any of 3-fluoropyrid-2-yl and4-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl.

If not otherwise specified or clear from context or unless otherwisespecified, the following terms herein have the following meanings:

-   -   (a) “Alkyl” as used herein is a saturated or unsaturated        hydrocarbon moiety, preferably saturated, preferably having one        to six carbon atoms, in some instances one to four carbon atoms,        which may be linear or branched, and may be optionally mono-,        di- or tri-substituted, e.g., with halogen (e.g., chloro or        fluoro), hydroxy, or carboxy.    -   (b) “Cycloalkyl” as used herein is a saturated or unsaturated        nonaromatic hydrocarbon moiety, preferably saturated, comprising        three to nine carbon atoms, in some instances three to seven        atoms, at least some of which form a nonaromatic mono- or        bicyclic, or bridged cyclic structure, and which may be        optionally substituted, e.g., with halogen (e.g., chloro or        fluoro), hydroxy or carboxy.    -   (c) “Heterocycloalkyl” is, unless otherwise indicated, saturated        or unsaturated nonaromatic hydrocarbon moiety, preferably        saturated, comprising three to nine carbon atoms, in some        instances three to seven atoms, at least some of which form a        nonaromatic mono- or bicyclic, or bridged cyclic structure,        wherein at least one carbon atom is replaced with N, O or S,        which heterocycloalkyl may be optionally substituted, e.g., with        halogen (e.g., chloro or fluoro), hydroxy or carboxy.    -   (d) “Aryl” as used herein is a mono or bicyclic aromatic        hydrocarbon, preferably phenyl. In some instances, aryl is        optionally substituted, e.g., with alkyl (e.g., methyl), halogen        (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl),        hydroxy, carboxy, or an additional aryl or heteroaryl (e.g.,        biphenyl or pyridylphenyl).    -   (e) “Heteroaryl” as used herein is an aromatic moiety wherein        one or more of the atoms making up the aromatic ring is sulfur,        oxygen or nitrogen rather than carbon, e.g., pyridyl or        thiadiazolyl which may be optionally substituted, e.g., with        alkyl, halogen, haloalkyl, hydroxy or carboxy.    -   (f) Wherein E is phenylene, the numbering is as follows:

-   -   (g) It is intended that wherein the substituents end in “ene”,        for example, alkylene, phenylene or arylalkylene, said        substituents are intended to bridge or be connected to two other        substituents. Therefore, methylene is intended to be —CH₂—,        ethylene is intended to be —CH₂—CH₂— and phenylene intended to        be —C₆H₄— and arylalkylene is intended to be —C₆H₄—CH₂— or        —CH₂—C₆H₄—.    -   (h) The Compounds of the Invention are intended to be numbered        as follows:

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.Similarly, the substituents defined for the Compounds of the Inventionare intended to result in stable compounds.

Compounds of the Invention, encompassing any of the compounds disclosedherein, e.g., optionally substituted 4,5,7,8-tetrahydro-(optionally4-oxo, 4-thioxo or 4-imino)-(1H or2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or 4,5,7,8,9-pentahydro-(1Hor 2H)-(optionally 4-oxo, 4-thioxo or4-imino)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, e.g., (1 or2 and/or 3 and/or 5)-substituted: 4,5,7,8-tetrahydro-(1H or2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine, 4,5,7,8-tetrahydro-(1H or2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-one,4,5,7,8-tetrahydro-(1H or2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione,4,5,7,8-tetrahydro-(1H or2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,4,5,7,8,9-pentahydro-(1H or2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine, 4,5,7,8,9-pentahydro-(1Hor 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-one,4,5,7,8,9-pentahydro-(1H or2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione,4,5,7,8,9-pentahydro-(1H or2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine compounds,e.g., Compounds of Formula I, e.g., any of formulae 1.1-1.111, orCompounds of any of Formulae II-VIII as described herein, may exist infree or salt form, e.g., as acid addition salts. In this specificationunless otherwise indicated, language such as “Compounds of theInvention” is to be understood as embracing the compounds in any form,for example free or acid addition salt form, or where the compoundscontain acidic substituents, in base addition salt form. The Compoundsof the Invention are intended for use as pharmaceuticals, thereforepharmaceutically acceptable salts are preferred. Salts which areunsuitable for pharmaceutical uses may be useful, for example, for theisolation or purification of free Compounds of the Invention or theirpharmaceutically acceptable salts, are therefore also included. Inparticular embodiment, the salt of the compounds of the invention is aformic acid addition salt.

Compounds of the Invention may in some cases also exist in prodrug form.A prodrug form is compound which converts in the body to a Compound ofthe Invention. For example when the Compounds of the Invention containhydroxy or carboxy substituents, these substituents may formphysiologically hydrolysable and acceptable esters. As used herein,“physiologically hydrolysable and acceptable ester” means esters ofCompounds of the Invention which are hydrolysable under physiologicalconditions to yield acids (in the case of Compounds of the Inventionwhich have hydroxy substituents) or alcohols (in the case of Compoundsof the Invention which have carboxy substituents) which are themselvesphysiologically tolerable at doses to be administered. Therefore,wherein the Compound of the Invention contains a hydroxy group, forexample, Compound-OH, the acyl ester prodrug of such compound, forexample, Compound-O—C(O)—C₁₋₄alkyl, can hydrolyze in the body to formphysiologically hydrolysable alcohol (Compound-OH) on the one hand andacid on the other (e.g., HOC(O)—C₁₋₄alkyl). Alternatively, wherein theCompound of the Invention contains a carboxylic acid, for example,Compound-C(O)OH, the acid ester prodrug of such compound, for example,Compound-C(O)O—C₁₋₄alkyl can hydrolyze to form Compound-C(O)OH andHO—C₁₋₄alkyl. As will be appreciated the term thus embraces conventionalpharmaceutical prodrug forms.

The invention also provides methods of making the Compounds of theInvention and methods of using the Compounds of the Invention fortreatment of diseases and disorders as set forth below (especiallytreatment of diseases characterized by reduced dopamine D1 receptorsignaling activity, such as Parkinson's disease, Tourette's Syndrome,Autism, fragile X syndrome, ADHD, restless leg syndrome, depression,cognitive impairment of schizophrenia, narcolepsy and diseases that maybe alleviated by the enhancement of progesterone-signaling such asfemale sexual dysfunction), or a disease or disorder such as psychosisor glaucoma). This list is not intended to be exhaustive and may includeother diseases and disorders as set forth below.

In another embodiment, the invention further provides a pharmaceuticalcomposition comprising a Compound of the Invention, in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

Methods of Making Compounds of the Invention

The compounds of the Invention and their pharmaceutically acceptablesalts may be made using the methods as described and exemplified hereinand by methods similar thereto and by methods known in the chemical art.Such methods include, but not limited to, those described below. If notcommercially available, starting materials for these processes may bemade by procedures, which are selected from the chemical art usingtechniques which are similar or analogous to the synthesis of knowncompounds. Various starting materials and/or Compounds of the Inventionmay be prepared using methods described in WO 2006/133261; WO2009/075784; PCT/US2009/06438 (or WO 2010/065148); PCT/US2009/006442 (orWO 2010/065151) and PCT/US2009/006439 (or WO 2010/065149). Allreferences cited herein are hereby incorporated by reference in theirentirety.

The Compounds of the Invention include their enantiomers,diastereoisomers and racemates, as well as their polymorphs, hydrates,solvates and complexes. Some individual compounds within the scope ofthis invention may contain double bonds. Representations of double bondsin this invention are meant to include both the E and the Z isomer ofthe double bond. In addition, some compounds within the scope of thisinvention may contain one or more asymmetric centers. This inventionincludes the use of any of the optically pure stereoisomers as well asany combination of stereoisomers.

As will be appreciated by those skilled in the art, the Compounds of theInvention may exhibit keto-enol tautomerization. Therefore, theinvention as defined in the present invention is to be understood asembracing both the structures as set forth herewith and their tautomericforms.

It is also intended that the Compounds of the Invention encompass theirstable and unstable isotopes. Stable isotopes are nonradioactiveisotopes which contain one additional neutron compared to the abundantnuclides of the same species (i.e., element). It is expected that theactivity of compounds comprising such isotopes would be retained, andsuch compound would also have utility for measuring pharmacokinetics ofthe non-isotopic analogs. For example, the hydrogen atom at a certainposition on the Compounds of the Invention may be replaced withdeuterium (a stable isotope which is non-radioactive). Examples of knownstable isotopes include, but not limited to, deuterium, ¹³C, ¹⁵N, ¹⁸O.Alternatively, unstable isotopes, which are radioactive isotopes whichcontain additional neutrons compared to the abundant nuclides of thesame species (i.e., element), e.g., ²³I, ¹³¹I, ¹²⁵I, ¹¹C, ¹⁸F, mayreplace the corresponding abundant species, e.g., I, C and Frespectively. Another example of useful isotope of the compound of theinvention is the ¹¹C isotope. These radio isotopes are useful forradio-imaging and/or pharmacokinetic studies of the compounds of theinvention. Methods of making isotopes of PDE1 inhibitors disclosed in WO2011/043816, the contents of which are incorporated by reference intheir entirety, may be used for making the isotopes of the compounds ofthe current invention.

Melting points are uncorrected and (dec) indicates decomposition.Temperature are given in degrees Celsius (° C.); unless otherwisestated, operations are carried out at room or ambient temperature, thatis, at a temperature in the range of 18-25° C. Chromatography meansflash chromatography on silica gel; thin layer chromatography (TLC) iscarried out on silica gel plates. NMR data is in the delta values ofmajor diagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard. Conventionalabbreviations for signal shape are used. Coupling constants (J) aregiven in Hz. For mass spectra (MS), the lowest mass major ion isreported for molecules where isotope splitting results in multiple massspectral peaks Solvent mixture compositions are given as volumepercentages or volume ratios. In cases where the NMR spectra arecomplex, only diagnostic signals are reported.

Terms and Abbreviations:

-   -   BOP=(Benzotriazole-1-yl-oxy)tris(dimethylamino)-phosphonium        hexafluorophosphate,    -   BuLi=n-butyllithium,    -   Bu^(t)OH=tert-butyl alcohol,    -   CAN=ammonium cerium (IV) nitrate,    -   DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene,    -   DIPEA=diisopropylethylamine,    -   DMF=N,N-dimethylformamide,    -   DMSO=dimethyl sulfoxide,    -   Et₂O=diethyl ether,    -   EtOAc=ethyl acetate,    -   equiv.=equivalent(s),    -   h=hour(s),    -   HPLC=high performance liquid chromatography,    -   K₂CO₃=potassium carbonate    -   LiHMDS=lithium bis(trimethylsilyl)amide    -   LDA=lithium diisopropylamide    -   MeOH=methanol,    -   NBS=N-bromosuccinimide,    -   NCS=N-chlorosuccinimide,    -   NaHCO₃=sodium bicarbonate,    -   NH₄OH=ammonium hydroxide,    -   Pd₂ (dba)₃=tris[dibenzylideneacetone]dipalladium(0)    -   PMB=p-methoxybenzyl,    -   POCl₃=phosphorous oxychloride,    -   SOCl₂=thionyl chloride,    -   TFA=trifluoroacetic acid,    -   TFMSA=trifluoromethanesulfonic acid    -   THF=tetrahydrofuran.

The synthetic methods in this invention are illustrated below. Thesignificances for the R groups are as set forth above for formula I-VIIIor any of formulae 1.1-1.111 unless otherwise indicated.

In an aspect of the invention, intermediate compounds of formula IIb canbe synthesized by reacting a compound of formula IIa with a dicarboxylicacid, acetic anhydride and acetic acid mixing with heat, e.g., to about90° C. for about 3 hours and then cooled:

-   -   wherein R¹ is methyl.

Intermediate IIc can be prepared by for example reacting intermediateIIb with for example a chlorinating compound such as POCl₃, sometimeswith small amounts of water and heat, e.g., heating to about 80° C. forabout 4 hours and then cooled:

Intermediate IId may be formed by reacting intermediate IIc with forexample a P¹-L in a solvent such as DMF and a base such as K₂CO₃, sodiumbicarbonate, cesium carbonate, sodium hydroxide, triethylamine,diisopropylethylamine or the like at room temperature or with heating:

-   -   wherein P¹ is a protective group [e.g., p-methoxybenzyl group        (PMB) or BOC]; L is a leaving group such as a halogen, mesylate,        or tosylate. Preferably, P¹ is PMB and the base is potassium        carbonate.

Intermediate IIe may be prepared by reacting intermediate IId withhydrazine or hydrazine hydrate in a solvent such as methanol and withheating, e.g. refluxed for about 4 hours and then cooled:

Intermediate IVa may be formed by for example reacting intermediate IIewith POCl₃ and DMF:

-   -   wherein R¹ is as defined previously, such as a methyl group.

Intermediate IVb may be formed by reacting intermediate IVa with forexample a R₅—X in a solvent such as DMF and a base such as K₂CO₃, sodiumbicarbonate, cesium carbonate, triethylamine or the like at roomtemperature or with heating (Reaction 1):

Intermediate IVc may be synthesized from intermediate IVb by removingthe protective group P¹ with an appropriate method. For example, if P¹is a PMB group, then it can be removed with CAN or TFA/TFMSA at roomtemperature (Reaction 2):

-   -   Wherein P¹ is BOC, the compound may be deprotected by using acid        such as hydrochloric acid or TFA.

Intermediate IVd can be prepared by reacting intermediate IVc with forexample a chlorinating compound such as POCl₃ and optionally withheating, e.g., reflux for about 2 days, or heated at 150˜200° C. forabout 5-10 min in a sealed vial with a microwave instrument and thencooled (Reaction 3):

Intermediate IVe can be formed by reacting a intermediate IVd with anamino alcohol under basic condition in a solvent such as DMF and heatedovernight then cooled (Reaction 4A):

-   -   Alternatively, intermediate IVe can be synthesized directly from        intermediate IVc by reacting with an amino alcohol and a        coupling reagent such as BOP in the presence of a base such as        DBU (Reaction 4B):

-   -   wherein all the substituents are as defined previously.

Intermediate IVf may be formed by reacting a compound of IVe with forexample a dehydrating/halogenating agent such as SOCl₂ in a solvent suchas CH₂Cl₂ at room temperature overnight or heated at 35° C. for severalhours, and then cooled (Reaction 5):

Intermediate IVg wherein X is halogen (e.g., chloro) may be formed byreacting intermediate IVf with for example a halogenating agent such ashexachloroethane, NCS, NBS, I₂ and a base such as LiHMDS in a solventsuch as THF at low temperature for several hours (Reaction 6).

The Compounds of the Invention may be formed by reacting intermediateIVg wherein X is halogen (e.g., chloro) with R₆—OH with heating(Reaction 7):

The Compounds of the Invention wherein Q is CH₂ may be prepared byreacting the Compounds of the Invention wherein Q is C(═O) with areducing agent, e.g., DIBAL-H or LAH, preferably DIBAL-H.

The Compounds of the Invention wherein Q is C(═S) may be prepared byreacting Compounds of the Invention wherein Q is C(═O) with P₄S₁₀ withP₄S₁₀ in a microwave vial in the presence of a base, e.g., pyridine, andoptionally heating the mixture to an elevated temperature, e.g., in amicrowave, e.g., to about 150° C.

Compounds of the Invention wherein Q is C(═N(R₂₀)) may be prepared byreacting a compound of the Invention wherein Q is C(═S) with NH₂ (R₂₀)in the presence of HgCl₂ upon heating.

Alternatively, the invention provides methods of making the Compounds ofthe Invention, for example, comprising reacting intermediate (I)-A withfor example R₅—X in a solvent such as DMF and a base such as K₂CO₃,cesium carbonate,

-   -   wherein all the substitutents are as defined previously in any        of Formulae I-VIII; X is a leaving group such as a halogen,        mesylate, or tosylate.

Reactions 1-6 referenced above are useful for preparing intermediatesuseful for the preparation of compounds of similar core structures,e.g., such as compounds described in WO 2006/133261, WO 2009/075784,PCT/US2009/006442 (or WO 2010/065151) and PCT/US2009/006439 (or WO2010/065149), the contents of each of which are incorporated byreference in their entirety. Therefore, the invention claims allintermediates disclosed herein, particularly compounds or intermediatesof formulae (IVa), (IVB), (IVc), (IVd), (IVe), (IVf) and (IVg).Reactions 1-6 referenced above are not only useful methods for preparingCompounds of the current Invention, but are also useful for preparingcompounds as disclosed in WO 2006/133261, WO 2009/075784,PCT/US2009/006442 (or WO 2010/065151) and PCT/US2009/006439 (or WO2010/065149). Therefore the invention provides a method of making acompound as disclosed in WO 2006/133261, WO 2009/075784,PCT/US2009/006442 (or WO 2010/065151) and PCT/US2009/006439 (or WO2010/065149), comprising the step(s) as described in any of Reactions1-6 wherein the intermediates are as defined in the respectiveapplications, for example, as defined in WO 2006/133261 or WO2009/075784. For example, Intermediate (IVc) as defined in WO2009/075784 is reacted with an amino alcohol and a coupling reagent suchas BOP in the presence of a base such as DBU as described in Reaction 4Bto form intermediate of formula (IVe) as defined in WO 2009/075784.Similarly, Intermediate (IVc) as defined in WO 2006/133261 may bereacted with an amino alcohol and a coupling reagent such as BOP in thepresence of a base such as DBU as described in Reaction 4B to formintermediate of formula (IVe) as defined in WO 2006/133261. Compound Iaas defined in WO 2006/133261 may be reacted with a halogenating agentsuch as hexachloroethane, NCS, NBS, I₂ and a base such as LiHMDS in asolvent such as THF at low temperature for several hours as described inReaction 6. The resulting product may then be reacted with R₆—NH₂wherein R₆ is as defined in WO 2006/133261 optionally in the presence ofa catalyst such as Pd₂ (pda)₃ and a ligand such as xantphos and a basesuch as potassium carbonate to yield the compound as defined in WO2006/133261.

Alternatively, Reactions 1-6 may be performed in different order, e.g.,wherein Reaction 6 is performed on intermediate (IVb), e.g., reactingintermediate (IVb) with a halogenating agent such as hexachloroethane,NCS, NBS, I₂ and optionally with a base such as LiHMDS in a solvent suchas THF at low temperature for several hours. The resulting product maythen be reacted with R₆—NH₂ wherein R₆ is as defined in WO 2006/133261optionally in the presence of a catalyst such as Pd₂ (pda)₃ and a ligandsuch as xantphos and a base such as potassium carbonate to yield thecompound as defined in WO 2006/133261. The resulting product is thendeprotected as described in Reaction 2 above. The deprotected product isreacted with an amino alcohol and a coupling reagent such as BOP in thepresence of a base such as DBU as described in Reaction 4B followed bythe reaction as described in Reaction 5.

Methods of Using Compounds of the Invention

The Compounds of the Invention are useful in the treatment of diseasescharacterized by disruption of or damage to cAMP and cGMP mediatedpathways, e.g., as a result of increased expression of PDE1 or decreasedexpression of cAMP and cGMP due to inhibition or reduced levels ofinducers of cyclic nucleotide synthesis, such as dopamine and nitricoxide (NO). By preventing the degradation of cAMP and cGMP by PDE1B,thereby increasing intracellular levels of cAMP and cGMP, the Compoundsof the Invention potentiate the activity of cyclic nucleotide synthesisinducers.

The invention provides methods of treatment of any one or more of thefollowing conditions:

-   -   (i) Neurodegenerative diseases, including Parkinson's disease,        restless leg tremors, dyskinesias, Huntington's disease,        Alzheimer's disease, and drug-induced movement disorders;    -   (ii) Mental disorders, including depression, attention deficit        disorder, attention deficit hyperactivity disorder, bipolar        illness, anxiety, sleep disorders, e.g., narcolepsy, cognitive        impairment, dementia, Tourette's syndrome, autism, fragile X        syndrome, psychostimulant withdrawal, and drug addiction;    -   (iii) Circulatory and cardiovascular disorders, including        cerebrovascular disease, stroke, congestive heart disease,        hypertension or pulmonary hypertension, and sexual dysfunction;    -   (iv) Respiratory and inflammatory disorders, including asthma,        chronic obstructive pulmonary disease, and allergic rhinitis, as        well as autoimmune and inflammatory diseases;    -   (v) Any disease or condition characterized by low levels of cAMP        and/or cGMP (or inhibition of cAMP and/or cGMP signaling        pathways) in cells expressing PDE1; and/or    -   (vi) Any disease or condition characterized by reduced dopamine        D1 receptor signaling activity,    -   comprising administering an effective amount of a Compound of        the Invention, e.g., any of Formulae I-VIII or 1.1-1.111, in        free or pharmaceutically acceptable salt form, to a human or        animal patient in need thereof.

In an especially preferred embodiment, the invention provides methods oftreatment or prophylaxis for narcolepsy. In this embodiment, PDE 1Inhibitors may be used as a sole therapeutic agent, but may also be usedin combination or for co-administration with other active agents. Thus,the invention further comprises a method of treating narcolepsycomprising administering simultaneously, sequentially, orcontemporaneously administering therapeutically effective amounts of

-   -   (i) a PDE 1 Inhibitor, e.g., any of Formulae I-VIII or        1.1-1.111, and    -   (ii) a compound to promote wakefulness or regulate sleep, e.g.,        selected from (a) central nervous system stimulants-amphetamines        and amphetamine like compounds, e.g., methylphenidate,        dextroamphetamine, methamphetamine, and pemoline; (b)        modafinil, (c) antidepressants, e.g., tricyclics (including        imipramine, desipramine, clomipramine, and protriptyline) and        selective serotonin reuptake inhibitors (including fluoxetine        and sertraline); and/or (d) gamma hydroxybutyrate (GHB).        -   in free or pharmaceutically acceptable salt form, to a human            or animal patient in need thereof. The Compounds of the            Invention may be used as a sole therapeutic agent or use in            combination for co-administered with another active agent.

In another embodiment, the invention further provides methods oftreatment or prophylaxis of a condition which may be alleviated by theenhancement of the progesterone signaling comprising administering aneffective amount of a Compound of the Invention, e.g., any of FormulaeI-VIII or 1.1-1.111, in free or pharmaceutically acceptable salt form,to a human or animal patient in need thereof. Disease or condition thatmay be ameliorated by enhancement of progesterone signaling include, butare not limited to, female sexual dysfunction, secondary amenorrhea(e.g., exercise amenorrhea, anovulation, menopause, menopausal symptoms,hypothyroidism), pre-menstrual syndrome, premature labor, infertility,for example infertility due to repeated miscarriage, irregular menstrualcycles, abnormal uterine bleeding, osteoporosis, autoimmune disease,multiple sclerosis, prostate enlargement, prostate cancer, andhypothyroidism. For example, by enhancing progesterone signaling, thePDE 1 inhibitors may be used to encourage egg implantation througheffects on the lining of uterus, and to help maintain pregnancy in womenwho are prone to miscarriage due to immune response to pregnancy or lowprogesterone function. The novel PDE 1 inhibitors, e.g., as describedherein, may also be useful to enhance the effectiveness of hormonereplacement therapy, e.g., administered in combination withestrogen/estradiol/estriol and/or progesterone/progestins inpostmenopausal women, and estrogen-induced endometrial hyperplasia andcarcinoma. The methods of the invention are also useful for animalbreeding, for example to induce sexual receptivity and/or estrus in anonhuman female mammal to be bred.

In this embodiment, PDE 1 Inhibitors may be used in the foregoingmethods of treatment or prophylaxis as a sole therapeutic agent, but mayalso be used in combination or for co-administration with other activeagents, for example in conjunction with hormone replacement therapy.Thus, the invention further comprises a method of treating disordersthat may be ameliorated by enhancement of progesterone signalingcomprising administering simultaneously, sequentially, orcontemporaneously administering therapeutically effective amounts of

-   -   (i) a PDE 1 Inhibitor, e.g., any of Formulae I-VIII or        1.1-1.111, and    -   (ii) a hormone, e.g., selected from estrogen and estrogen        analogues (e.g., estradiol, estriol, estradiol esters) and        progesterone and progesterone analogues (e.g., progestins)        -   in free or pharmaceutically acceptable salt form, to a human            or animal patient in need thereof.

The invention also provides a method for enhancing or potentiatingdopamine D1 intracellular signaling activity in a cell or tissuecomprising contacting said cell or tissue with an amount of a Compoundof the Invention, e.g., any of Formulae I-VIII or 1.1-1.111, sufficientto inhibit PDE1B activity, e.g., PDE1A or PDE1B activity.

The invention also provides a method for treating a PDE1-related,especially PDE1B-related disorder, a dopamine D1 receptor intracellularsignaling pathway disorder, or disorders that may be alleviated by theenhancement of the progesterone signaling pathway in a patient in needthereof comprising administering to the patient an effective amount of aCompound of the Invention, e.g., any of Formulae I-VIII or 1.1-1.111, inthat inhibits PDE1B, wherein PDE1B activity modulates phosphorylation ofDARPP-32 and/or the GluR1 AMPA receptor.

In another aspect, the invention also provides a method for thetreatment for glaucoma or elevated intraocular pressure comprisingtopical administration of a therapeutically effective amount of aphosphodiesterase type I (PDE1) Inhibitor of the Invention, in free orpharmaceutically acceptable salt form, in an ophthalmically compatiblecarrier to the eye of a patient in need thereof. However, treatment mayalternatively include a systemic therapy. Systemic therapy includestreatment that can directly reach the bloodstream, or oral methods ofadministration, for example.

The invention further provides a pharmaceutical composition for topicalophthalmic use comprising a PDE1 inhibitor; for example an ophthalmicsolution, suspension, cream or ointment comprising a PDE1 Inhibitor ofthe Invention, in free or ophthalmologically acceptable salt form, incombination or association with an ophthalmologically acceptable diluentor carrier.

Optionally, the PDE1 inhibitor may be administered sequentially orsimultaneously with a second drug useful for treatment of glaucoma orelevated intraocular pressure. Where two active agents are administered,the therapeutically effective amount of each agent may be below theamount needed for activity as monotherapy. Accordingly, a subthresholdamount (i.e., an amount below the level necessary for efficacy asmonotherapy) may be considered therapeutically effective and also mayalso be referred alternatively as an effective amount. Indeed, anadvantage of administering different agents with different mechanisms ofaction and different side effect profiles may be to reduce the dosageand side effects of either or both agents, as well as to enhance orpotentiate their activity as monotherapy.

The invention thus provides the method of treatment of a conditionselected from glaucoma and elevated intraocular pressure comprisingadministering to a patient in need thereof an effective amount, e.g., asubthreshold amount, of an agent known to lower intraocular pressureconcomitantly, simultaneously or sequentially with an effective amount,e.g., a subthreshold amount, of a PDE1 Inhibitor of the Invention, infree or pharmaceutically acceptable salt form, such that amount of theagent known to lower intraocular pressure and the amount of the PDE1inhibitor in combination are effective to treat the condition.

In one embodiment, one or both of the agents are administered topicallyto the eye. Thus the invention provides a method of reducing the sideeffects of treatment of glaucoma or elevated intraocular pressure byadministering a reduced dose of an agent known to lower intraocularpressure concomitantly, simultaneously or sequentially with an effectiveamount of a PDE1 inhibitor. However, methods other than topicaladministration, such as systemic therapeutic administration, may also beutilized.

The optional additional agent or agents for use in combination with aPDE1 inhibitor may, for example, be selected from the existing drugscomprise typically of instillation of a prostaglandin, pilocarpine,epinephrine, or topical beta-blocker treatment, e.g. with timolol, aswell as systemically administered inhibitors of carbonic anhydrase, e.g.acetazolamide. Cholinesterase inhibitors such as physostigmine andechothiopate may also be employed and have an effect similar to that ofpilocarpine. Drugs currently used to treat glaucoma thus include, e.g.,

-   -   1. Prostaglandin analogs such as latanoprost (Xalatan),        bimatoprost (Lumigan) and travoprost (Travatan), which increase        uveoscleral outflow of aqueous humor. Bimatoprost also increases        trabecular outflow.    -   2. Topical beta-adrenergic receptor antagonists such as timolol,        levobunolol (Betagan), and betaxolol, which decrease aqueous        humor production by the ciliary body.    -   3. Alpha₂-adrenergic agonists such as brimonidine (Alphagan),        which work by a dual mechanism, decreasing aqueous production        and increasing uveo-scleral outflow.    -   4. Less-selective sympathomimetics like epinephrine and        dipivefrin (Propine) increase outflow of aqueous humor through        trabecular meshwork and possibly through uveoscleral outflow        pathway, probably by a beta₂-agonist action.    -   5. Miotic agents (parasympathomimetics) like pilocarpine work by        contraction of the ciliary muscle, tightening the trabecular        meshwork and allowing increased outflow of the aqueous humour.    -   6. Carbonic anhydrase inhibitors like dorzolamide (Trusopt),        brinzolamide (Azopt), acetazolamide (Diamox) lower secretion of        aqueous humor by inhibiting carbonic anhydrase in the ciliary        body.    -   7. Physostigmine is also used to treat glaucoma and delayed        gastric emptying.

For example, the invention provides pharmaceutical compositionscomprising a PDE1 Inhibitor of the Invention and an agent selected from(i) the prostanoids, unoprostone, latanoprost, travoprost, orbimatoprost; (ii) an alpha adrenergic agonist such as brimonidine,apraclonidine, or dipivefrin and (iii) a muscarinic agonist, such aspilocarpine. For example, the invention provides ophthalmic formulationscomprising a PDE-1 Inhibitor of the Invention together with bimatoprost,abrimonidine, brimonidine, timolol, or combinations thereof, in free orophthamologically acceptable salt form, in combination or associationwith an ophthamologically acceptable diluent or carrier. In addition toselecting a combination, however, a person of ordinary skill in the artcan select an appropriate selective receptor subtype agonist orantagonist. For example, for alpha adrenergic agonist, one can select anagonist selective for an alpha 1 adrenergic receptor, or an agonistselective for an alpha₂ adrenergic receptor such as brimonidine, forexample. For a beta-adrenergic receptor antagonist, one can select anantagonist selective for either β₁, or β₂, or β₃, depending on theappropriate therapeutic application. One can also select a muscarinicagonist selective for a particular receptor subtype such as M₁-M₅.

The PDE 1 inhibitor may be administered in the form of an ophthalmiccomposition, which includes an ophthalmic solution, cream or ointment.The ophthalmic composition may additionally include anintraocular-pressure lowering agent.

In yet another example, the PDE-1 Inhibitors disclosed may be combinedwith a subthreshold amount of an intraocular pressure-lowering agentwhich may be a bimatoprost ophthalmic solution, a brimonidine tartrateophthalmic solution, or brimonidine tartrate/timolol maleate ophthalmicsolution.

In addition to the above-mentioned methods, it has also beensurprisingly discovered that PDE1 inhibitors are useful to treatpsychosis, for example, any conditions characterized by psychoticsymptoms such as hallucinations, paranoid or bizarre delusions, ordisorganized speech and thinking, e.g., schizophrenia, schizoaffectivedisorder, schizophreniform disorder, psychotic disorder, delusionaldisorder, and mania, such as in acute manic episodes and bipolardisorder. Without intending to be bound by any theory, it is believedthat typical and atypical antipsychotic drugs such as clozapineprimarily have their antagonistic activity at the dopamine D2 receptor.PDE1 inhibitors, however, primarily act to enhance signaling at thedopamine D1 receptor. By enhancing D1 receptor signaling, PDE1inhibitors can increase NMDA receptor function in various brain regions,for example in nucleus accumbens neurons and in the prefrontal cortex.This enhancement of function may be seen for example in NMDA receptorscontaining the NR2B subunit, and may occur e.g., via activation of theSrc and protein kinase A family of kinases.

Therefore, the invention provides a new method for the treatment ofpsychosis, e.g., schizophrenia, schizoaffective disorder,schizophreniform disorder, psychotic disorder, delusional disorder, andmania, such as in acute manic episodes and bipolar disorder, comprisingadministering a therapeutically effective amount of aphosphodiesterase-1 (PDE1) Inhibitor of the Invention, in free orpharmaceutically acceptable salt form, to a patient in need thereof.

PDE 1 Inhibitors may be used in the foregoing methods of treatmentprophylaxis as a sole therapeutic agent, but may also be used incombination or for co-administration with other active agents. Thus, theinvention further comprises a method of treating psychosis, e.g.,schizophrenia, schizoaffective disorder, schizophreniform disorder,psychotic disorder, delusional disorder, or mania, comprisingadministering simultaneously, sequentially, or contemporaneouslyadministering therapeutically effective amounts of:

-   -   (i) a PDE 1 Inhibitor of the invention, in free or        pharmaceutically acceptable salt form; and    -   (ii) an antipsychotic, e.g.,        -   Typical antipsychotics, e.g.,            -   Butyrophenones, e.g. Haloperidol (Haldol, Serenace),                Droperidol (Droleptan);            -   Phenothiazines, e.g., Chlorpromazine (Thorazine,                Largactil), Fluphenazine (Prolixin), Perphenazine                (Trilafon), Prochlorperazine (Compazine), Thioridazine                (Mellaril, Melleril), Trifluoperazine (Stelazine),                Mesoridazine, Periciazine, Promazine, Triflupromazine                (Vesprin), Levomepromazine (Nozinan), Promethazine                (Phenergan), Pimozide (Orap);            -   Thioxanthenes, e.g., Chlorprothixene, Flupenthixol                (Depixol, Fluanxol), Thiothixene (Navane),                Zuclopenthixol (Clopixol, Acuphase);        -   Atypical antipsychotics, e.g.,            -   Clozapine (Clozaril), Olanzapine (Zyprexa), Risperidone                (Risperdal), Quetiapine (Seroquel), Ziprasidone                (Geodon), Amisulpride (Solian), Paliperidone (Invega),                Aripiprazole (Abilify), Bifeprunox; norclozapine,            -   in free or pharmaceutically acceptable salt form, to a                patient in need thereof.

In a particular embodiment, the Compounds of the Invention areparticularly useful for the treatment or prophylaxis of schizophrenia.

Compounds of the Invention, in free or pharmaceutically acceptable saltform, are particularly useful for the treatment of Parkinson's disease,schizophrenia, narcolepsy, glaucoma and female sexual dysfunction.

In still another aspect, the invention provides a method of lengtheningor enhancing growth of the eyelashes by administering an effectiveamount of a prostaglandin analogue, e.g., bimatoprost, concomitantly,simultaneously or sequentially with an effective amount of a PDE1inhibitor of the Invention, in free or pharmaceutically acceptable saltform, to the eye of a patient in need thereof.

In yet another aspect, the invention provides a method for the treatmentor prophylaxis of traumatic brain injury comprising administering atherapeutically effective amount of a PDE1 inhibitor of the invention,in free or pharmaceutically acceptable salt form, to a patient in needthereof. Traumatic brain injury (TBI) encompasses primary injury as wellas secondary injury, including both focal and diffuse brain injuries.Secondary injuries are multiple, parallel, interacting andinterdependent cascades of biological reactions arising from discretesubcellular processes (e.g., toxicity due to reactive oxygen species,overstimulation of glutamate receptors, excessive influx of calcium andinflammatory upregulation) which are caused or exacerbated by theinflammatory response and progress after the initial (primary) injury.Abnormal calcium homeostasis is believed to be a critical component ofthe progression of secondary injury in both grey and white matter. For areview of TBI, see Park et al., CMAJ (2008) 178(9):1163-1170, thecontents of which are incorporated herein in their entirety. Studieshave shown that the cAMP-PKA signaling cascade is downregulated afterTBI and treatment of PDE IV inhibitors such as rolipram to raise orrestore cAMP level improves histopathological outcome and decreasesinflammation after TBI. As Compounds of the present invention is a PDE1inhibitor, it is believed that these compounds are also useful for thetreatment of TBI, e.g., by restoring cAMP level and/or calciumhomeostasis after traumatic brain injury.

The present invention also provides

-   -   (i) a Compound of the Invention, e.g., any of Formulae I-VIII or        1.1-1.111, as hereinbefore described, in free or        pharmaceutically acceptable salt form for example for use in any        method or in the treatment of any disease or condition as        hereinbefore set forth,    -   (ii) the use of a Compound of the Invention, e.g any of Formulae        I-VIII or 1.1-1.111, as hereinbefore described, in free or        pharmaceutically acceptable salt form, in the manufacture of a        medicament for treating any disease or condition as hereinbefore        set forth,    -   (iii) a pharmaceutical composition comprising a Compound of the        Invention, e.g., any of Formulae I-VIII or 1.1-1.111, as        hereinbefore described, in free or pharmaceutically acceptable        salt form, in combination or association with a pharmaceutically        acceptable diluent or carrier, and    -   (iv) a pharmaceutical composition comprising a Compound of the        Invention, e.g., any of Formulae I-VIII or 1.1-1.111, as        hereinbefore described, in free or pharmaceutically acceptable        salt form, in combination or association with a pharmaceutically        acceptable diluent or carrier for use in the treatment of any        disease or condition as hereinbefore set forth.

Therefore, the invention provides use of a Compound of the Invention,e.g., any of Formulae I-VIII or 1.1-1.111, as hereinbefore described, infree or pharmaceutically acceptable salt form, or a Compound of theInvention in a pharmaceutical composition form, (the manufacture of amedicament) for the treatment or prophylactic treatment of the followingdiseases: Parkinson's disease, restless leg tremors, dyskinesias,Huntington's disease, Alzheimer's disease, and drug-induced movementdisorders; depression, attention deficit disorder, attention deficithyperactivity disorder, bipolar illness, anxiety, sleep disorder,narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism,fragile X syndrome, psychostimulant withdrawal, and/or drug addiction;cerebrovascular disease, stroke, congestive heart disease, hypertensionor pulmonary hypertension, and/or sexual dysfunction; asthma, chronicobstructive pulmonary disease, and/or allergic rhinitis, as well asautoimmune and inflammatory diseases; and/or female sexual dysfunction,exercise amenorrhea, anovulation, menopause, menopausal symptoms,hypothyroidism, pre-menstrual syndrome, premature labor, infertility,irregular menstrual cycles, abnormal uterine bleeding, osteoporosis,multiple sclerosis, prostate enlargement, prostate cancer,hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma;and/or any disease or condition characterized by low levels of cAMPand/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) incells expressing PDE1, and/or by reduced dopamine D1 receptor signalingactivity; and/or any disease or condition that may be ameliorated by theenhancement of progesterone signaling.

The invention also provides use of a Compound of the Invention, in freeor pharmaceutically acceptable salt form, (the manufacture of amedicament) for the treatment or prophylactic treatment of:

-   -   a) glaucoma or elevated intraocular pressure,    -   b) psychosis, for example, any conditions characterized by        psychotic symptoms such as hallucinations, paranoid or bizarre        delusions, or disorganized speech and thinking, e.g.,        schizophrenia, schizoaffective disorder, schizophreniform        disorder, psychotic disorder, delusional disorder, and mania,        such as in acute manic episodes and bipolar disorder, or    -   c) traumatic brain injury.

The phrase “Compounds of the Invention” or “PDE 1 inhibitors of theInvention” encompasses any and all of the compounds disclosed herewith,e.g., an optionally substituted:

-   4,5,7,8-tetrahydro-(1H or    2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,-   4,5,7,8-tetrahydro-(1H or    2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-one,-   4,5,7,8-tetrahydro-(1H or    2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione,-   4,5,7,8-tetrahydro-(1H or    2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,-   4,5,7,8,9-pentahydro-(1H or    2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine,-   4,5,7,8,9-pentahydro-(1H or    2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-one,-   4,5,7,8,9-pentahydro-(1H or    2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione,-   4,5,7,8,9-pentahydro-(1H or    2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,-   any of Formulae I-VIII or 1.1-1.111,

in free or (pharmaceutically) salt form.

The words “treatment” and “treating” are to be understood accordingly asembracing prophylaxis and treatment or amelioration of symptoms ofdisease as well as treatment of the cause of the disease.

For methods of treatment, the word “effective amount” is intended toencompass a therapeutically effective amount to treat a specific diseaseor disorder.

The term “pulmonary hypertension” is intended to encompass pulmonaryarterial hypertension.

The term “patient” include human or non-human (i.e., animal) patient. Inparticular embodiment, the invention encompasses both human andnonhuman. In another embodiment, the invention encompasses nonhuman. Inother embodiment, the term encompasses human.

The term “comprising” as used in this disclosure is intended to beopen-ended and does not exclude additional, unrecited elements or methodsteps.

Compounds of the Invention are in particular useful for the treatment ofParkinson's disease, narcolepsy and female sexual dysfunction.

Compounds of the Invention, in free or pharmaceutically acceptable saltform, may be used as a sole therapeutic agent, but may also be used incombination or for co-administration with other active agents. Forexample, as Compounds of the Invention potentiate the activity of D1agonists, such as dopamine, they may be simultaneously, sequentially, orcontemporaneously administered with conventional dopaminergicmedications, such as levodopa and levodopa adjuncts (carbidopa, COMTinhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics,e.g., in the treatment of a patient having Parkinson's disease. Inaddition, the novel PDE 1 inhibitors, e.g., as described herein, mayalso be administered in combination with estrogen/estradiol/estrioland/or progesterone/progestins to enhance the effectiveness of hormonereplacement therapy or treatment of estrogen-induced endometrialhyperplasia or carcinoma.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compound of the Invention used, the mode ofadministration, and the therapy desired. Compounds of the Invention maybe administered by any suitable route, including orally, parenterally,transdermally, or by inhalation, but are preferably administered orally.In general, satisfactory results, e.g. for the treatment of diseases ashereinbefore set forth are indicated to be obtained on oraladministration at dosages of the order from about 0.01 to 2.0 mg/kg. Inlarger mammals, for example humans, an indicated daily dosage for oraladministration will accordingly be in the range of from about 0.75 to150 mg, conveniently administered once, or in divided doses 2 to 4times, daily or in sustained release form. Unit dosage forms for oraladministration thus for example may comprise from about 0.2 to 75 or 150mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of theInvention, together with a pharmaceutically acceptable diluent orcarrier therefor.

Pharmaceutical compositions comprising Compounds of the Invention may beprepared using conventional diluents or excipients and techniques knownin the galenic art. Thus oral dosage forms may include tablets,capsules, solutions, suspensions and the like.

EXAMPLES

The synthetic methods for various Compounds of the Present Invention areillustrated below. Other compounds of the Invention and their salts maybe made using the methods as similarly described below and/or by methodssimilar to those generally described in the detailed description and bymethods known in the chemical art.

Example 1(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-phenoxy-2-(4-(1H-pyrazol-1-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

(a)2-(4-(1H-pyrazol-1-yl)benzyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

A suspension of7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(667 mg, 2.33 mmol), 1-(4-(bromomethyl)phenyl)-1H-pyrazole (552 mg, 2.33mmol) and K₂CO₃ (644 mg, 4.66 mmol) in DMF (20 mL) is stirred at roomtemperature overnight. Solvent is removed under reduced pressure. Theobtained residue is treated with methylene chloride (400 mL), and thenwashed with water three times. The organic phase is evaporated todryness to give 1.0 g of crude product, which is used in the next stepwithout further purification. MS (ESI) m/z 443.2 [M+H]⁺.

(b)2-(4-(1H-pyrazol-1-yl)benzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione

TFA (3.0 mL) is added into a suspension of2-(4-(1H-pyrazol-1-yl)benzyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(1.0 g, 2.3 mmol) in methylene chloride (6 mL) to give a tan solution,and then TFMSA (0.85 mL) is added. The reaction mixture is stirred atroom temperature overnight, and then diluted with 100 mL of methylenechloride, followed by adding 50 mL of water to precipitate product outof solution. After filtration, the obtained solids are washed with watertwice, and then dried under vacuum to give the first crop of crudeproduct. The organic phase in the filtrate is washed with water twice,and then evaporated to remove solvents to the second crop of crudeproduct. The obtained crude product is combined (0.94 g in total) and isused in the next step without further purification. MS (ESI) m/z 323.1[M+H]⁺.

(c)2-(4-(1H-pyrazol-1-yl)benzyl)-6-((1R,2R)-2-hydroxycyclopentylamino)-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

DBU (1.2 mL, 7.9 mmol) is added into a suspension of crude2-(4-(1H-pyrazol-1-yl)benzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dioneTFMSA salt (620 mg, 1.3 mmol) and BOP (1.7 g, 3.9 mmol) in THF (12 mL)to give a yellow solution. The mixture is stirred at room temperaturefor 5 min, and then (1R,2R)-2-aminocyclopentanol hydrochloride (542 mg,3.9 mmol) is added. The reaction mixture is stirred at room temperaturefor 4 hours. After removal of solvent, the residue is treated withmethylene chloride, and then washed with saturated NaHCO₃ aqueoussolution three times. The organic phase is evaporated to dryness to give2.1 g salt-containing crude product, which is used in the next stepwithout further purification. MS (ESI) m/z 406.2 [M+H]⁺.

(d)(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(1H-pyrazol-1-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

Thionyl chloride (180 μL, 2.47 mmol) is added dropwise to a solution ofcrude2-(4-(1H-pyrazol-1-yl)benzyl)-6-((1R,2R)-2-hydroxycyclopentylamino)-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(2.0 g, 4.9 mmol) in DMF (10 mL). The reaction mixture is stirred atroom temperature for 20 min. DMF is removed under reduced pressure. Theobtained residue is treated with methylene chloride (200 mL), and thenwashed with 5% NaHCO₃ aqueous solution three times (3×80 mL). Theorganic phase is evaporated to dryness to give 1.1 g crude product,which is used in the next step without further purification. MS (ESI)m/z 388.2 [M+H]⁺.

(e)(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-(1H-pyrazol-1-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

1.0M LiHMDS (4.25 mL, 4.25 mml) in THF is added dropwise into a solutionof crude(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(1H-pyrazol-1-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one(1.1 g) and hexachloroethane (403 mg, 1.7 mmol) in methylene chloride(20 mL). The reaction mixture is stirred at room temperature for 20 min,and then diluted with methylene chloride (130 mL), followed by washingwith water four times (4×50 mL). The organic phase is evaporated todryness to give 754 mg of crude product with 84% purity, which is usedin the next step without further purification. MS (ESI) m/z 422.2[M+H]⁺.

(f)(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-phenoxy-2-(4-(1H-pyrazol-1-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

Crude(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-(1H-pyrazol-1-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one(50 mg), phenol (45 mg, 0.47 mmol) and Cs₂CO₃ (77 mg, 0.24 mmol) areplaced in a microwave vial, and then dioxane (1 mL) is added. The vialis sealed and heated in a Biotage microwave instrument at 130° C. for 40min. The reaction mixture is then purified with a semi-preparative HPLCto give 11 mg of product as off-white solid (purity: 97%). MS (ESI) m/z480.2 [M+H]⁺.

Example 2(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-(4-fluorophenoxy)-5-methyl-2-(4-(pyridin2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

The synthesis method is analogous to example 1 wherein2-(4-(chloromethyl)phenyl)pyridine is added in step (a) instead of1-(4-(bromomethyl)phenyl)-1H-pyrazole; and 4-fluorophenol is added instep (f) instead of phenol. MS (ESI) m/z 509.2 [M+H]⁺

Example 37,8-dihydro-5,7,7-trimethyl-3-phenoxy-2-(4-(6-Fluoro-pyridin-2-yl)-benzyl)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

The synthesis method is analogous to example 1 wherein2-(4-(chloromethyl)phenyl)-6-fluoropyridine is added in step (a) insteadof 1-(4-(bromomethyl)phenyl)-1H-pyrazole; and2-amino-2-methylpropan-1-ol is added in step (c) instead of(1R,2R)-2-aminocyclopentanol hydrochloride. MS (ESI) m/z 497.2 [M+H]⁺

Example 4(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(4-fluorophenoxy)-2-(4-(1H-pyrazol-1-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

The synthesis method is analogous to example 1 wherein 4-fluorophenol isadded in step (f) instead of phenol. MS (ESI) m/z 498.3 [M+H]⁺

Example 5(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-(cyclohexyloxy)-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one(25 mg, 0.055 mmol), cyclohexanol (0.5 mL) and Cs₂CO₃ (27 mg, 0.083mmol) are placed in a microwave vial. The vial is sealed and heated in aBiotage microwave instrument at 140° C. for an hour. The reactionmixture is then purified with a semi-preparative HPLC to give 14 mg ofproduct as white solids (purity: 98%). MS (ESI) m/z 515.2 [M+H]⁺.

Example 6(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-(cyclopentyloxy)-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

The synthesis method is analogous to Example 5 wherein cyclopentanol isadded instead of cyclohexanol. MS (ESI) m/z 501.3 [M+H]⁺

Example 7(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-isobutoxy-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

The synthesis method is analogous to Example 5 wherein2-methylpropan-1-ol is added instead of cyclohexanol. MS (ESI) m/z 489.3[M+H]⁺

Example 8(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-isopropoxy-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

The synthesis method is analogous to Example 5 wherein propan-2-ol isadded instead of cyclohexanol. MS (ESI) m/z 475.2 [M+H]⁺

Example 9(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-phenoxy-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one(26 mg, 0.058 mmol), phenol (10.8 mg, 0.12 mmol) and K₂CO₃ (24 mg, 0.17mmol) are placed in a microwave vial, and then dioxane (0.5 mL) isadded. The vial is sealed and heated in a Biotage microwave instrumentat 150° C. for three hours. The reaction mixture is then purified with asemi-preparative HPLC to give 21 mg of product as white solids (purity:98.6%). MS (ESI) m/z 509.2 [M+H]⁺.

Example 10(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-(4-fluorophenoxy)-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

The synthesis method is analogous to Example 9 wherein 4-fluorophenol isadded instead of phenol. MS (ESI) m/z 527.2 [M+H]⁺

Example 11(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-(3-chlorophenoxy)-5-methyl-2-(4-(6-fluoro-pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one

The synthesis method is analogous to Example 9 wherein 3-chlorophenol isadded instead of phenol. MS (ESI) m/z 543.2 [M+H]⁺

Example 12 Measurement of PDE1B Inhibition In Vitro Using IMAPPhosphodiesterase Assay Kit

Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin dependentphosphodiesterase enzyme that converts cyclic guanosine monophosphate(cGMP) to 5′-guanosine monophosphate (5′-GMP). PDE1B can also convert amodified cGMP substrate, such as the fluorescent moleculecGMP-fluorescein, to the corresponding GMP-fluorescein. The generationof GMP-fluorescein from cGMP-fluorescein can be quantitated, using, forexample, the IMAP (Molecular Devices, Sunnyvale, Calif.)immobilized-metal affinity particle reagent.

Briefly, the IMAP reagent binds with high affinity to the free5′-phosphate that is found in GMP-fluorescein and not incGMP-fluorescein. The resulting GMP-fluorescein-IMAP complex is largerelative to cGMP-fluorescein. Small fluorophores that are bound up in alarge, slowly tumbling, complex can be distinguished from unboundfluorophores, because the photons emitted as they fluoresce retain thesame polarity as the photons used to excite the fluorescence.

In the phosphodiesterase assay, cGMP-fluorescein, which cannot be boundto IMAP, and therefore retains little fluorescence polarization, isconverted to GMP-fluorescein, which, when bound to IMAP, yields a largeincrease in fluorescence polarization (Δmp). Inhibition ofphosphodiesterase, therefore, is detected as a decrease in Δmp.

Enzyme Assay

-   -   Materials: All chemicals are available from Sigma-Aldrich (St.        Louis, Mo.) except for IMAP reagents (reaction buffer, binding        buffer, FL-GMP and IMAP beads), which are available from        Molecular Devices (Sunnyvale, Calif.).    -   Assay: 3′,5′-cyclic-nucleotide-specific bovine brain        phosphodiesterase (Sigma, St. Louis, Mo.) is reconstituted with        50% glycerol to 2.5 U/ml. One unit of enzyme will hydrolyze 1.0        μmole of 3′,5′-cAMP to 5′-AMP per min at pH 7.5 at 30° C. One        part enzyme is added to 1999 parts reaction buffer (30 μM CaCl₂,        10 U/ml of calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10        mM MgCl₂, 0.1% BSA, 0.05% NaN₃) to yield a final concentration        of 1.25 mU/ml. 99 μl of diluted enzyme solution is added into        each well in a flat bottom 96-well polystyrene plate to which 1        μl of test compound dissolved in 100% DMSO is added. Selected        Compounds of the Invention are mixed and pre-incubated with the        enzyme for 10 min at room temperature.

The FL-GMP conversion reaction is initiated by combining 4 parts enzymeand inhibitor mix with 1 part substrate solution (0.225 μM) in a384-well microtiter plate. The reaction is incubated in dark at roomtemperature for 15 min. The reaction is halted by addition of 60 μl ofbinding reagent (1:400 dilution of IMAP beads in binding buffersupplemented with 1:1800 dilution of antifoam) to each well of the384-well plate. The plate is incubated at room temperature for 1 hour toallow IMAP binding to proceed to completion, and then placed in anEnvision multimode microplate reader (PerkinElmer, Shelton, Conn.) tomeasure the fluorescence polarization (Δmp).

A decrease in GMP concentration, measured as decreased Δmp, isindicative of inhibition of PDE activity. IC₅₀ values are determined bymeasuring enzyme activity in the presence of 8 to 16 concentrations ofcompound ranging from 0.0037 nM to 80,000 nM and then plotting drugconcentration versus ΔmP, which allows IC₅₀ values to be estimated usingnonlinear regression software (XLFit; IDBS, Cambridge, Mass.).

The Compounds of the Invention may be selected and tested in an assay asdescribed or similarly described herein for PDE1 inhibitory activity.The exemplified compounds of the invention generally have IC₅₀ values ofless than or equal to 100 nM, some less than 10 nM, some less than 1 nM,against PDE1A and/or PDE1B.

Example 13 PDE1 Inhibitor Effect on Sexual Response in Female Rats

The effect of PDE1 inhibitors on Lordosis Response in female rats may bemeasured as described in Mani, et al., Science (2000) 287: 1053.Ovariectomized and cannulated wild-type rats are primed with 2 μgestrogen followed 24 hours later by intracerebroventricular (icy)injection of progesterone (2 μg), PDE1 inhibitors of the presentinvention (0.1 mg, 1.0 mg or 2.5 mg) or sesame oil vehicle (control).The rats may be tested for lordosis response in the presence of malerats. Lordosis response is quantified by the lordosis quotient(LQ=number of lordosis/10 mounts×100).

What is claimed is:
 1. A PDE 1 inhibitor compound, wherein said compoundis a compound of Formula I:

wherein (i) Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or CH₂; (ii) L is a —O—;(iii) R₁ is H or C₁₋₄alkyl; (iv) R₄ is H or C₁₋₄alkyl and R₂ and R₃ are,independently: H, C₁₋₆alkyl optionally substituted with halo or hydroxy,aryl, heteroaryl, (optionally hetero)arylC₁₋₆alkyl, or R₂ and R₃together with the carbon to which they are attached form a 3- to6-membered ring; or R₂ is H and R₃ and R₄ together form a di-, tri- ortetra-methylene bridge; (v) R₅ is a) -D-E-F, wherein: D is a singlebond, C₁₋₄alkylene or —C(═O)—; E is a single bond, C₁₋₄alkylene,arylene, arylC₁₋₄alkylene or heteroarylene; and F is H, aryl,heteroaryl, halo, C₁₋₄alkyl, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxy,—C(O)—R₁₅, —N(R₁₆)(R₁₇), —S(O)₂R₂₁, C₃₋₇cycloalkyl orheteroC₃₋₇cycloalkyl; wherein D, E and F are independently andoptionally substituted with one or more group selected from: halo,C₁₋₄alkyl, haloC₁₋₄alkyl, and C₁₋₄alkoxy; b) heteroarylC₁₋₄alkyloptionally substituted with haloC₁₋₄alkyl; or c) attached to one of thenitrogen atoms on the pyrazolo portion of Formula I and is a moiety ofFormula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂are independently H, halogen, —C₁₋₄alkyl-N(R₂₂)(R₂₃), or—C₁₋₄alkyl-heterC₃₋₈cycloalkyl, and R₁₀ is: hydrogen, halogen,C₁₋₄alkyl, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxy, C₃₋₇cycloalkyl,hetC₃₋₇cycloalkyl, C₁₋₄haloalkyl, aryl, heteroaryl, arylcarbonyl,C₁₋₄alkylsulfonyl, aminosulfonyl, heteroarylcarbonyl, C₁₋₄alkylcarbonyl,C₁₋₄alkoxycarbonyl, —C(O)OH, haloC₁₋₄alkoxycarbony, —C(O)N(R₁₈)(R₁₉), or—C₁₋₄alkyl-N(R₁₈)(R₁₉), wherein the aryl, heteroaryl, cycloalkyl andheterocycloalkyl are independently and optionally substituted with oneor more group selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyland —SH; provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀,respectively, is not present; (vi) R₆ is C₁₋₄alkyl, C₃₋₇cycloalkyl,aryl, heteroaryl, or arylC₁₋₄alkyl, wherein the aryl or heteroaryl isoptionally substituted with one or more group selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₈cycloalkyl, (vii) n=0 or 1;(viii) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,independently, H, C₁₋₄alkyl, aryl, heteroaryl, (optionallyhetero)arylC₁₋₄alkoxy or (optionally hetero)arylC₁₋₄alkyl or R₁₃ or R₁₄can form a di-, tri- or tetramethylene bridge with R₂ or R₄; (ix) R₁₅ isC₁₋₄alkyl, haloC₁₋₄alkyl, —OH, —OC₁₋₄alkyl, aryl or —N(R₁₆)(R₁₇); (x)R₁₆ and R₁₇ are independently H or C₁₋₄alkyl; (xi) R₁₈ and R₁₉ areindependently H, C₁₋₄alky, C₃₋₈cycloalkyl, heteroC₃₋₈cycloalkyl, aryl,or heteroaryl, wherein said aryl or heteroaryl is optionally substitutedwith one or more group selected from: halo, hydroxy, C₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkoxy, aryl, heteroaryl, and C₃₋₈cycloalkyl; (xii)R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl; (xiii) R₂₁ is C₁₋₆alkyl or—N(R₁₈)(R₁₉); (xiv) R₂₂ and R₂₃ are independently H or C₁₋₄alkyl, infree or salt form.
 2. A PDE1 inhibitor compound, wherein said compoundis selected form any one of the following: A) a Compound of Formula II:

wherein (i) Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or CH₂; (ii) L is a —O—;(iii) R₁ is H or C₁₋₄alkyl; (iv) R₄ is H or C₁₋₄alkyl and R₂ and R₃ are,independently: H, C₁₋₆alkyl optionally substituted with halo or hydroxy,aryl, heteroaryl, (optionally hetero)arylC₁₋₆alkoxy, or (optionallyhetero)arylC₁₋₆alkyl, or R₂ and R₃ together with the carbon to whichthey are attached form a 3- to 6-membered ring; or R₂ is H and R₃ and R₄together form a di-, tri- or tetramethylene bridge; (v) R₅ is a) -D-E-F,wherein D is C₁₋₄alkylene; E is arylene; and F is aryl, heteroaryl,C₃₋₇cycloalkyl, or heteroC₃₋₇cycloalkyl, wherein F is optionallysubstituted with one or more halo or C₁₋₆alkyl; or b) attached to one ofthe nitrogen atoms on the pyrazolo portion of Formula II and is a moietyof Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂are independently H, halogen, and R₁₀ is C₃₋₇cycloalkyl,hetC₃₋₇cycloalkyl, aryl, or heteroaryl, wherein the aryl, heteroaryl,cycloalkyl and heterocycloalkyl are independently and optionallysubstituted with one or more halo, C₁₋₄alkyl, provided that when X, Y,or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is not present; (vi) R₆is C₁₋₄alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, arylC₁₋₄alkyl, whereinthe aryl or heteroaryl is optionally substituted with one or more halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₈cycloalkyl; (vii) n=0 or 1; (viii)when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are, independently, Hor C₁₋₄alkyl, aryl, heteroaryl, (optionally hetero)arylC₁₋₄alkoxy,(optionally hetero)arylC₁₋₄alkyl or R₁₃ or R₁₄ can form a di-, tri- ortetramethylene bridge with R₂ or R₄; (ix) R₂₀ is H, C₁₋₄alkyl orC₃₋₇cycloalkyl, in free or salt form; B) a compound of Formula III:

wherein (i) Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or CH₂; (ii) L is a —O—;(iii) R₁ is H or C₁₋₄alkyl; (iv) R₄ is H or C₁₋₄alkyl and R₂ and R₃ are,independently: H, C₁₋₆alkyl optionally substituted with halo or hydroxy,aryl, heteroaryl, (optionally hetero)arylC₁₋₆alkoxy, (optionallyhetero)arylC₁₋₆alkyl, or R₂ and R₃ together with the carbon to whichthey are attached form a 3- to 6-membered ring; or R₂ is H and R₃ and R₄together form a di-, tri- or tetramethylene bridge; (v) R₅ is a) -D-E-F,wherein D is C₁₋₄alkylene; E is arylene; and F is aryl, heteroaryl,C₃₋₇cycloalkyl, or heteroC₃₋₇cycloalkyl, wherein F is optionallysubstituted with one or more halo or C₁₋₆alkyl; or b) attached to one ofthe nitrogen atoms on the pyrazolo portion of Formula III and is amoiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂are independently H or halogen, and R₁₀ is C₃₋₇cycloalkyl,hetC₃₋₇cycloalkyl, aryl, or heteroaryl, wherein the aryl, heteroaryl,cycloalkyl and heterocycloalkyl are independently and optionallysubstituted with one or more halo or C₁₋₄alkyl, provided that when X, Y,or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is not present; (vi) R₆is: C₁₋₄alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, wherein the aryl orheteroaryl is optionally substituted with one or more halo, hydroxy orC₁₋₆alkyl, (vii) n=0 or 1; (viii) when n=1, A is —C(R₁₃R₁₄)—, whereinR₁₃ and R₁₄, are, independently, H or C₁₋₄alkyl, aryl, heteroaryl,(optionally hetero)arylC₁₋₄alkoxy, (optionally hetero)arylC₁₋₄alkyl orR₁₃ or R₁₄ can form a di-, tri- or tetramethylene bridge with R₂ or R₄;(i) R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl, in free or salt form; C) acompound of Formula IV:

wherein: (i) Q is —C(═S)—, —C(═N(R₂₀))—, —C(═O)— or CH₂; (ii) L is a—O—; (iii) R₁ is H or C₁₋₄alkyl; (iv) R₅ is a) -D-E-F, wherein D isC₁₋₄alkylene; E is arylene; F is aryl, heteroaryl, C₃₋₇cycloalkyl, orheteroC₃₋₇cycloalkyl, wherein F is optionally substituted with one ormore halo or C₁₋₆alkyl; or b) attached to one of the nitrogen atoms onthe pyrazolo portion of Formula IV and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂are independently H or halogen, and R₁₀ is C₃₋₇cycloalkyl,hetC₃₋₇cycloalkyl, aryl, or heteroaryl, wherein the aryl, heteroaryl,cycloalkyl and heterocycloalkyl are independently and optionallysubstituted with one or more halo, C₁₋₄alkyl, provided that when X, Y,or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is not present; (v) R₆is: C₁₋₄alkyl, C₃₋₇cycloalkyl, aryl, heteroaryl, wherein the aryl orheteroaryl is optionally substituted with one or more halo, hydroxy orC₁₋₆alkyl, (ii) R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl, in free or saltform; D) a compound of Formula V:

wherein: (i) Q is —C(═O)—; (ii) L is —O—; (iii) R₁ is C₁₋₄alkyl; (iv) R₅is attached to one of the nitrogen atoms on the pyrazolo portion ofFormula V and is a moiety of Formula A

wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are H, and R₁₀ is:hetC₃₋₇cycloalkyl, aryl, or heteroaryl, wherein the aryl, heteroaryl,cycloalkyl and heterocycloalkyl are independently and optionallysubstituted with one or more halo, C₁₋₄alkyl; (v) R₆ is C₃₋₇cycloalkyl,aryl, heteroaryl, arylC₁₋₄alkyl, wherein the aryl or heteroaryl isoptionally substituted with one or more halo, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, C₃₋₈cycloalkyl, in free or salt form; E) a compound ofFormula VI:

wherein: (i) Q is —C(═O)—; (ii) L is —O—; (iii) R₁ is C₁₋₄alkyl; (iv) R₅is attached to one of the nitrogen atoms on the pyrazolo portion ofFormula VI and is a moiety of Formula A

wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are H, and R₁₀ isselected from piperidinyl, pyrrolidinyl, pyridyl, diazolyl,6-fluoropyrid-2-yl, 1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,1-ethylpiperidin-1-yl or 1-methylpiperidin-2-yl; (v) R₆ isC₃₋₇cycloalkyl, aryl, heteroaryl, arylC₁₋₄alkyl, wherein the aryl orheteroaryl is optionally substituted with one or more halo, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₈cycloalkyl, in free or salt form; F) acompound of Formula VII:

wherein: (i) Q is —C(═O)—; (ii) L is —O—; (iii) R₁ is C₁₋₄alkyl; (iv) R₅is attached to one of the nitrogen atoms on the pyrazolo portion ofFormula VII and is a moiety of Formula A

wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are H, and R₁₀ isselected from piperidinyl, pyrrolidinyl, pyridyl, diazolyl,6-fluoropyrid-2-yl, 1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,1-ethylpiperidin-1-yl or 1-methylpiperidin-2-yl; (v) R₆ is selected fromcyclopentyl, cyclohexyl, phenyl, 3-chlorophenyl or 4-fluorophenyl, infree or salt form; G) a compound of Formula VIII:

wherein: (i) Q is —C(═O)—; (ii) L is —O—; (iii) R₁ is C₁₋₄alkyl; (iv) R₅is attached to one of the nitrogen atoms on the pyrazolo portion ofFormula VIII and is a moiety of Formula A

wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are H, and R₁₀ ispyrid-2-yl, 6-fluoropyrid-2-yl, 1-methylpyrrolidin-3-yl,1-methylpyrrolidin-2-yl, 1-ethylpiperidin-1-yl or1-methylpiperidin-2-yl; (v) R₆ is phenyl or 4-fluorophenyl, in free orsalt form.
 3. The Compound according to claim 1, wherein R₁₀ is selectedfrom any of 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,4-fluoropyrid-2-yl, in free or salt form.
 4. The Compound according toclaim 1, wherein said compound is selected from any of the following:

in free or salt form.
 5. A pharmaceutical composition comprising acompound according to claim 1, in free or pharmaceutically acceptablesalt form, in admixture with a pharmaceutically acceptable diluent orcarrier.
 6. The compound according claim 1, wherein said compound is acompound of Formula V:

wherein: (i) Q is —C(═O)—; (ii) L is —O—; (iii) R₁ is C₁₋₄alkyl; (iv) R₅is attached to one of the nitrogen atoms on the pyrazolo portion ofFormula V and is a moiety of Formula A

wherein X, Y and Z are C, and R₈, R₉, R₁₁ and R₁₂ are H, and R₁₀ is:hetC₃₋₇cycloalkyl, aryl, or heteroaryl, wherein the aryl, heteroaryl,cycloalkyl and heterocycloalkyl are independently and optionallysubstituted with one or more halo, C₁₋₄alkyl; (v) R₆ is C₃₋₇cycloalkyl,aryl, heteroaryl, arylC₁₋₄alkyl, wherein the aryl or heteroaryl isoptionally substituted with one or more halo, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, C₃₋₈cycloalkyl, in free or salt form.
 7. The Compoundaccording to claim 1, wherein R₅ is -D-E-F and D is C₁₋₄alkylene, E isarylene, and F is heteroaryl optionally substituted with one or moregroup selected from halo, C₁₋₄alkyl, haloC₁₋₄alkyl, and C₁₋₄alkoxy, infree or salt form.
 8. The compound according to claim 1, wherein saidcompound is selected from:

in free or salt form.